Leading Edge

Review

A Tale of Chromatin and Transcription

in 100 Structures
Patrick Cramer1,*
1Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany

*Correspondence: [email protected]
http://dx.doi.org/10.1016/j.cell.2014.10.047

To celebrate a century of X-ray crystallography, I describe how 100 crystal structures influenced
chromatin and transcription research.

Introduction duplex was solved only after DNA synthesis methods became
When Max von Laue first illuminated a crystal with X-rays 100 available (Wing et al., 1980) (Figure 1). Crystal structures of
years ago, it was unclear what the obtained diffraction pattern DNA in A-form (Shakked et al., 1981) and Z-form (Wang et al.,
meant. William Henry Bragg and his son Lawrence, however, 1979) highlighted the sequence-dependent conformational flex-
soon realized that X-ray diffraction provided information about ibility of DNA.
the inner structure of crystals. After decades of elaboration, In eukaryotic nuclei, DNA is packaged with histone proteins
X-ray crystallography advanced to become the most widely into chromatin. The fundamental unit of chromatin, the nucleo-
used method for the determination of 3D structures. Its ap- some core particle, was elucidated structurally in 1984 at a res-
plication to biological macromolecules fostered the deve- olution of 7 Å (Richmond et al., 1984). When the resolution
lopment of molecular biology in the second half of the 20th reached 2.8 Å, a detailed view of the nucleosome emerged
century. Crystallography defined biological paradigms such that revealed the DNA conformation and DNA interactions with
as molecular recognition, enzymatic catalysis, and allosteric histones (Luger et al., 1997). The nucleosome core structure
regulation. confirmed the structure of the free histone octamer (Arents
Until about 30 years ago, researchers could still follow publica- et al., 1991). It further showed that the histone protein tails
tion of all new crystal structures of biomolecules. But then the emerged between and around DNA duplexes to become avail-
pace at which new structures were solved increased rapidly able for interactions with other nucleosomes or chromatin.
due to the advent of new enabling techniques. Proteins were ob- The structure of higher-order chromatin is dynamic, but a
tained in recombinant form, and nucleic acids were synthesized complex of four nucleosomes could be crystallized and showed
in large quantities. Crystals were cryo-cooled to slow down ra- two stacks of nucleosomes and DNA that zigzagged between
diation damage. Synchrotron X-ray sources improved, and fast them (Schalch et al., 2005). Electron microscopy revealed how
X-ray detection devices emerged. Modern computers and better such tetranucleosome units may be arranged within a 30 nm
software for structure determination became available. By now, fiber of chromatin (Song et al., 2014) and provided evidence
100,000 structures have been deposited in the protein database. for helical order in such fibers (Scheffer et al., 2011). Another
Many of these revealed the inner workings of molecular ma- electron microscopic study provided an alternative fiber model
chines, allowing researchers to rationalize phenotypes of muta- (Robinson et al., 2006). These results explained how extended
tions and to engineer biological processes. DNA molecules can be packaged in the cell nucleus but also pro-
Crystal structures can be like landmarks. They can guide us on vided models for how chromatin regulates the accessibility of
our way toward a better understanding of a biological process genes and their transcription. Whereas a compact chromatin
(Shi, 2014 [this issue of Cell]). Landmark structures not only structure can cause gene repression, gene activation requires
disclose some of life’s secrets, but they also open up new fron- chromatin opening and assembly of the transcription machinery
tiers. Here, I describe many of the structures that I consider to be at the promoter.
landmark structures in the biology of chromatin, transcription,
and epigenetics. I hope the resulting list of about 100 crystallo- How DNA Is Recognized
graphic structures, along with several structures obtained by To enable transcription, cells use transcription factors that bind
other methods, exemplifies how structural information influ- to specific DNA sites. The first crystal structures of transcription
enced the community and led to new concepts. factors included the bacterial catabolite activator protein CAP
(McKay and Steitz, 1981) (Figure 1) and the bacteriophage
How DNA Is Structured lambda proteins cro (Anderson et al., 1981) and repressor
The proposal of the double-helical structure of DNA relied on (Pabo and Lewis, 1982). These structures contained helix-turn-
X-ray diffraction patterns of DNA fibers obtained in the middle helix regions that were involved in DNA binding and led to the
of the last century (Watson and Crick, 1953) (Figure 1). The direct concept of DNA-binding protein motifs. The studies of the bacte-
observation of a nucleic acid duplex, however, had to await the riophage proteins required protein overexpression because
crystal structure of a transfer RNA (tRNA) from yeast in 1974 these transcription factors could not be isolated from natural
(Robertus et al., 1974) (Figure 1). The structure of a B-DNA sources in quantities required for structural studies.

Cell 159, November 20, 2014 ª2014 Elsevier Inc. 985

Figure 1. A Selection of Landmark Crystal Structures in the Biology of Chromatin and Transcription
From left to right, the depicted structures are yeast tRNA, a DNA duplex, the bacterial transcription factor CAP, the bacteriophage 434 repressor protein in
complex with DNA, the eukaryotic TATA-binding protein TBP, the nucleosome, the bacterial RNA polymerase, the histone acetyltransferase Gcn5, the eukaryotic
RNA polymerase 10-subunit core enzyme, the complete 12-subunit RNA polymerase II complex in complex with transcription factor TFIIS, and an archaeal Swi/
Snf-type ATPase resembling the catalytic subunit found in many chromatin remodeling complexes. DNA is shown in blue, and proteins are depicted as ribbon
models in different colors. For details, please refer to the text.

Structures of DNA-bound transcription factors led to the (Reményi et al., 2003). Crystallography also led to a model
concept of sequence-specific DNA recognition. DNA complexes of an ‘‘enhanceosome’’ containing eight transcription factors
of the repressor proteins from bacteriophages 434 (Anderson bound to DNA (Panne et al., 2007). Here, binding of one factor in-
et al., 1987) (Figure 1) and lambda (Jordan and Pabo, 1988) duces a DNA conformation that promotes binding of a neigh-
and of the 434 cro protein (Wolberger et al., 1988) revealed boring factor.
protein helices bound in the DNA major groove. DNA-binding Transcription factors can also bend DNA dramatically. The
helices were also observed in structures of homeodomains bacterial CAP protein bends DNA by 90 degrees to enable spe-
(Kissinger et al., 1990; Otting et al., 1990; Qian et al., 1989). In cific DNA recognition (Schultz et al., 1991). The eukaryotic TATA
a ‘‘leucine zipper’’ of the GCN4 factor, protein helices in the box-binding protein (TBP) also introduces a 90 degree bend into
DNA major groove were extended and used for factor dimeriza- DNA (Kim et al., 1993a, 1993b). The integration host factor (Rice
tion (Ellenberger et al., 1992; König and Richmond, 1993). The et al., 1996) and the mitochondrial transcription factor A (Ngo
transcription factors recognized target sequences via interac- et al., 2011; Rubio-Cosials et al., 2011) can even bend DNA by
tions of amino acid residues with DNA base edges. Such ‘‘direct 180 degrees, inducing a U-turn. To achieve DNA bending, pro-
readout’’ can be complemented by ‘‘indirect readout’’ of the teins can use two strategies. They can insert amino acid residues
DNA conformation via protein-DNA backbone contacts (Lesser like wedges between DNA base pairs to disrupt base stacking
et al., 1990; Otwinowski et al., 1988). and may also neutralize backbone charges on one side of
Later protein-DNA complex structures revealed a variety of DNA, which induces bending due to the repulsion of phosphates
DNA-binding structural motifs. The transcription factor NF-kB on the opposite strand.
uses a b barrel fold to contact DNA via protein loops (Becker
et al., 1998; Ghosh et al., 1995; Müller et al., 1995). Transcription How DNA Binding Is Regulated
factors of the zinc finger family recognize DNA with small protein Crystallography further established concepts that explained
folds that are stabilized by zinc ions (Fairall et al., 1993; Luisi bacterial gene regulation. In the trp operon, the Trp repressor
et al., 1991; Marmorstein et al., 1992; Pavletich and Pabo, protein inhibits expression of enzymes required for tryptophan
1991). Zinc fingers were later used for the design of proteins biosynthesis when enough of the amino acid is available. The
with new DNA-binding specificities (Choo et al., 1994). This cata- structure of the Trp repressor revealed a homodimer with a
lyzed the development of protein and genome engineering as DNA-binding helix in each monomer (Schevitz et al., 1985). Bind-
new research fields. Zinc fingers were also present in Klf4 ing of the regulator tryptophan alters the relative position of
(Schuetz et al., 2011), which, together with transcription factors the two helices to enable DNA binding and gene repression
Oct4, Sox2, and c-Myc, enables reprogramming of the genome (Otwinowski et al., 1988). These studies also showed that water
and generation of induced pluripotent stem cells. molecules in the protein-DNA interface may contribute to
Crystallography also showed how transcription factors bind to sequence-specific DNA recognition.
adjacent DNA sites for combinatorial gene regulation. The DNA- Many transcription factors contain not only a DNA-binding
bound structures of yeast MATa2 interacting with MATa1 (Li domain but also additional domains that can activate transcrip-
et al., 1995) and with MCM1 (Tan and Richmond, 1998) revealed tion or bind other transcription factors or small-molecule regula-
factor-factor interactions that underlie synergistic DNA binding. tors. In the bacterial lac operon, the Lac repressor protein binds
This concept held for human transcription factors (Piper et al., DNA to control the expression of enzymes involved in lactose
1999). Oct4 and Sox2 can also bind to neighboring DNA sites metabolism. The lac repressor contains a domain that binds

986 Cell 159, November 20, 2014 ª2014 Elsevier Inc.

the regulator lactose (Friedman et al., 1995) and a domain that transition from transcription initiation to elongation (Schwing-
binds DNA (Bell and Lewis, 2000; Lewis et al., 1996). The regu- hammer et al., 2013).
lator allosterically changes the orientation of the DNA-binding
domains, leading to DNA dissociation and gene activation. How DNA Is Transcribed in Cells: Multisubunit RNA
Eukaryotic transcription factors are generally also modular. Polymerases
The nuclear receptor for the hormone estrogen comprises a The first structures of cellular RNA polymerases were obtained
DNA-binding domain (Schwabe et al., 1993) and a hormone- at the turn of the millennium. The structure of bacterial RNA
binding domain (Brzozowski et al., 1997). Binding of estrogen polymerase from Thermus aquaticus (Zhang et al., 1999) was
influences receptor dimerization and its interaction with other followed by the structure of yeast RNA polymerase II (Pol II),
factors that regulate transcription. The tumor suppressor p53 which synthesizes messenger RNA (Cramer et al., 2000, 2001)
contains a tetramerization domain that clamps four p53 subunits (Figure 1). The structures revealed functional elements and
together (Clore et al., 1994) and a DNA-binding domain that har- enabled structure-function analysis of cellular transcription.
bors tumorigenic mutations that can impair DNA binding (Cho They also suggested that catalysis followed a two-metal ion
et al., 1994). mechanism (Cramer et al., 2000), as proposed for all nucleotide
Transcription factors are often regulated by nuclear localiza- polymerases (Steitz and Steitz, 1993). Comparison of bacterial
tion. For example, the inhibitory protein I-kB retains the tran- and eukaryotic RNA polymerases revealed a conserved multisu-
scription factor NF-kB in the cytoplasm by masking its nuclear bunit architecture and an active center cleft with a flexible bridge
localization sequence (Huxford et al., 1998). External signals helix for the translocation of the polymerase relative to DNA.
remove I-kB, leading to nuclear import of NF-kB, DNA binding, The structure of a Pol II transcription elongation complex
and gene activation. Similarly, external signals trigger phosphor- showed that the polymerase clamp domain closed over a
ylation of cytosolic STAT transcription factors (Becker et al., DNA-RNA hybrid of eight to nine base pairs during transcription
1998), which leads to factor dimerization, nuclear import, DNA elongation and suggested the basis for nucleic acid strand sep-
binding, and gene activation. aration during transcription (Gnatt et al., 2001). Later structures
of bacterial RNA polymerase and Pol II transcription elongation
How DNA Directs RNA Synthesis: Single-Subunit complexes with bound nucleoside triphosphate substrate (Vas-
RNA Polymerases sylyev et al., 2007; Wang et al., 2006) revealed that folding of
It took until the late 1990s to obtain a crystallographic view of the polymerase trigger loop closed the active site and sug-
transcription. The shape of the single-subunit DNA-dependent gested mechanisms of substrate selection. The same mecha-
RNA polymerase from bacteriophage T7 was observed in a me- nisms likely occur in archaeal RNA polymerases, which show
dium-resolution crystallographic study (Sousa et al., 1993). The a remarkable similarity to Pol II (Hirata et al., 2008; Korkhin
crystal structure of T7 RNA polymerase revealed an active center et al., 2009).
cleft and a domain that binds promoter DNA and enables The first structure of Pol II with a bound transcription factor, the
sequence-specific initiation of RNA synthesis (Jeruzalmi and elongation factor TFIIS, showed that a single ‘‘tunable’’ active
Steitz, 1998; Cheetham et al., 1999). In the structure of a T7 site was used both for RNA synthesis and RNA cleavage and
RNA polymerase transcribing complex, the DNA template strand indicated the mechanism of proofreading during transcription
formed a hybrid duplex with a transcript of three nucleotides at (Kettenberger et al., 2003) (Figure 1). Electron microscopy of
the active site (Cheetham and Steitz, 1999). This suggested that an analogous bacterial complex revealed a similar topology
the polymerase could only hold a three base pair DNA-RNA (Opalka et al., 2003). The structure of an ‘‘arrested’’ Pol II elonga-
hybrid, but later structures of the T7 elongation complex revealed tion complex with a backtracked RNA provided insights into how
extensive refolding of the polymerase, which then accommo- TFIIS rescues polymerase that stalled during transcription
dated a seven to eight base pair hybrid (Tahirov et al., 2002; Yin (Cheung and Cramer, 2011). Crystal structures of a second eu-
and Steitz, 2002). karyotic RNA polymerase, Pol I, showed that a subunit corre-
These studies established many concepts in DNA-directed sponding to TFIIS was located at the active center of this enzyme
RNA synthesis. They highlighted the importance of promoter (Engel et al., 2013; Fernández-Tornero et al., 2013).
recognition and showed how ribonucleotide substrates are Transcription is coordinated with cotranscriptional events
selected over deoxyribonucleotides to prevent synthesis of such as RNA processing. This coordination is to a large extent
DNA. Addition of nucleotides to the RNA occurs in two steps achieved by binding of factors to the flexible C-terminal domain
by first binding the substrate nucleoside triphosphate to a prein- (CTD) of Pol II. Changes in CTD phosphorylation lead to an ex-
sertion site and then moving it to the insertion site for catalysis change of protein factors during transcription. The first struc-
(Temiakov et al., 2004). Details of RNA synthesis were revealed tures of CTD peptides bound to CTD-binding proteins showed
by X-ray studies of the single-subunit RNA polymerase from that the CTD adopts multiple conformations and revealed the ba-
bacteriophage N4 (Basu and Murakami, 2013). sis for phosphorylation-specific binding (Fabrega et al., 2003;
Eukaryotic cells also contain a single-subunit RNA poly- Meinhart and Cramer, 2004; Verdecia et al., 2000). Crystallog-
merase, the polymerase transcribing the mitochondrial genome. raphy also revealed the mechanisms and the determinants for
Mitochondrial RNA polymerase structurally resembles T7 RNA substrate specificity of CTD kinases (Baumli et al., 2012; Baumli
polymerase but contains an additional region for promoter bind- et al., 2008; Bösken et al., 2014; Lolli et al., 2004; Schneider et al.,
ing (Ringel et al., 2011). In contrast to T7 RNA polymerase, mito- 2011; Tahirov et al., 2010) and CTD phosphatases (Ghosh et al.,
chondrial RNA polymerase, however, does not refold during the 2008; Kamenski et al., 2004; Xiang et al., 2010).

Cell 159, November 20, 2014 ª2014 Elsevier Inc. 987

How Transcription Starts How Transcription Initiation Is Regulated
For the initiation of transcription, RNA polymerases cooperate Bacterial transcription can be regulated by direct interactions of
with initiation factors to locate and open promoter DNA. The transcription factors with the general transcription machinery
structure of the Pol II initiation factor TBP revealed a saddle- and DNA. The CAP factor activates transcription by binding
shaped molecule (Nikolov et al., 1992) (Figure 1) that bound DNA and an adjacent domain of the polymerase, thereby recruit-
the DNA minor groove and bent DNA by 90 degrees (Kim ing the polymerase to the promoter (Benoff et al., 2002). Simi-
et al., 1993a, 1993b). The resulting TBP-DNA complex can re- larly, a protein of bacteriophage lambda activates transcription
cruit initiation factors TFIIA (Geiger et al., 1996; Tan et al., 1996) by binding to DNA and an adjacent domain of sigma (Jain
and TFIIB (Nikolov et al., 1995) on either side. Electron micro- et al., 2004). Eukaryotic transcription factors normally bind to co-
scopy revealed the overall architectures of the large multipro- activator complexes, which then bind the general transcription
tein initiation factors TFIID (Andel et al., 1999; Bieniossek machinery. Coactivator binding requires activation domains,
et al., 2013; Cianfrocco et al., 2013; Leurent et al., 2002) and which are often unstructured in their free state but can adopt
TFIIH (Chang and Kornberg, 2000; Gibbons et al., 2012; Schultz short helical structures upon coactivator binding (Brzovic et al.,
et al., 2000). Crystal structures for individual parts of TFIID, 2011; Kussie et al., 1996; Radhakrishnan et al., 1997). Vice versa,
TFIIE, TFIIF, and TFIIH were reported, including an archaeal ho- a coactivator can also form a a helix to bind a transcription factor
molog of the ATPase in TFIIH (Fan et al., 2006) that functions in (Shiau et al., 1998).
DNA opening. Many transcription factors bind to the coactivator complex
An understanding of transcription initiation, however, had to Mediator, which consists of 25–35 subunits arranged in four
await structures of initiation factor complexes with RNA poly- modules. The crystal structure of the Mediator head module re-
merases. An initial structure of a partial Pol II-TFIIB complex vealed an intricate fold with surfaces for interactions with Pol II
(Bushnell et al., 2004) was consistent with crosslinking results and other Mediator modules (Imasaki et al., 2011; Larivière
(Chen and Hahn, 2003) and revealed a domain of TFIIB that et al., 2012; Robinson et al., 2012). Recent electron microscopy
bound Pol II to recruit it to the promoter. The structure of revealed the central location of the head module within the over-
the Pol II-TFIIB complex (Kostrewa et al., 2009; Liu et al., all Mediator architecture (Tsai et al., 2014; Wang et al., 2014). The
2010) enabled modeling of initiation complexes with closed mechanisms by which Mediator influences transcription remain
double-stranded and open DNA. A subsequent structure of to be explored, but there is evidence for a conformational change
a Pol II-TFIIB complex with bound DNA and an initial RNA in Mediator induced by binding of a transcription activator
transcript showed that TFIIB alters the polymerase active (Meyer et al., 2010; Taatjes et al., 2002).
site to allosterically activate RNA synthesis (Sainsbury et al., Transcription initiation is also regulated by methylation of DNA
2013). upstream of the promoter. In higher cells, this often occurs in
Bacterial transcription initiation relies on sigma factors. The CpG islands, which are DNA regions enriched for CpG dinucleo-
structure of a free sigma factor revealed its modular nature tides. Hypermethylation of CpG islands generally leads to tran-
(Malhotra et al., 1996). Structures of RNA polymerase with scription repression. In a structure of a methyltransferase-DNA
bound sigma factor (Murakami et al., 2002b; Vassylyev et al., substrate complex, the target base was flipped out of the DNA
2002) and with sigma factor and promoter DNA (Murakami double helix and inserted into the enzyme’s active site (Klima-
et al., 2002a) showed that sigma factor bridges between poly- sauskas et al., 1994). A human DNA methyltransferase uses
merase and the promoter and suggested how sigma factor do- additional domains to ensure that only hemimethylated CpG di-
mains recognize DNA sequence elements. When promoter nucleotides undergo methylation after replication, as seen in the
DNA is unwound, one sigma factor domain traps the nontem- enzyme-DNA complex structure (Song et al., 2011; Song et al.,
plate single strand of DNA (Feklistov and Darst, 2011). An alter- 2012).
native sigma factor is able to stabilize a flipped-out base from
the nontemplate strand during DNA melting (Campagne et al., How Chromatin Regulates Transcription
2014). Structures of bacterial transcription initiation complexes To make chromatin accessible for transcription, remodeling
showed how RNA polymerase and sigma factor cooperate to complexes use ATP hydrolysis to change nucleosome position
recognize promoter sequences, unwind DNA, and ‘‘preorgan- and structure. Many remodelers contain a Swi/Snf family
ize’’ the template strand for RNA chain initiation (Zhang et al., ATPase that induces DNA translocation with respect to histones
2012). (Dürr et al., 2005; Thomä et al., 2005) (Figure 1). A combination of
The initiation factors sigma and TFIIB perform similar func- structural techniques provided the architecture of chromatin re-
tions, including DNA binding and opening and defining the start modelers ISW1a (Yamada et al., 2011), INO80 (Saravanan et al.,
site of transcription. Comparison of bacterial and eukaryotic 2012; Tosi et al., 2013), and SWR1 (Nguyen et al., 2013) and indi-
structures showed that sigma factor and TFIIB interact with cated how these machines bind nucleosomes, although the
roughly the same parts of their RNA polymerases but have unre- structure of the ‘‘remodeled nucleosome state’’ has remained
lated folds, arguing for convergent evolution. Recently, electron elusive. Remodeling complexes not only bind nucleosomes—
microscopy and crosslinking provided the location of additional they can also be regulated by nucleosomes allosterically (Clapier
initiation factors in human and yeast Pol II initiation complexes and Cairns, 2012; Hauk et al., 2010; Racki et al., 2014).
(Grünberg et al., 2012; He et al., 2013; Mühlbacher et al., 2014; Proper nucleosome assembly by histone chaperones is
Murakami et al., 2013), enabling further crystallographic studies required to repress cryptic transcription that can produce aber-
of transcription initiation. rant RNAs from nonpromoter regions. X-ray studies unraveled

988 Cell 159, November 20, 2014 ª2014 Elsevier Inc.

chaperone structures and showed that chaperones disrupt domain also binds a methylated lysine residue by trapping it
histone interfaces or mimic nucleosomal DNA to prevent promis- into an aromatic cage that is lined with residues mutated in can-
cuous histone interactions prior to their assembly into nucleo- cer (Li et al., 2006; Peña et al., 2006). The pockets in reader and
somes (Elsässer et al., 2012; English et al., 2006; Hondele eraser proteins were consequently explored for drug design (Fil-
et al., 2013; Hu et al., 2011; Park and Luger, 2006). Certain as- ippakopoulos et al., 2010). Multiple histone marks can be read
sembly factors incorporate histone variants into nucleosomes by a single reader domain (Morinière et al., 2009) or by combina-
at specific sites. The histone variant H2A.Z changes nucleosome torial binding of readers (Jacobson et al., 2000; Tsai et al., 2010;
structure at active promoters (Suto et al., 2000) and is removed Xi et al., 2011). Multiple histone marks influence transcription
by a specific chaperone (Obri et al., 2014), and nucleosomes activity, for example, via the initiation factor TFIID that binds his-
containing the centromeric histone H3 variant are apparently de- tone tails with marks for active transcription (Vermeulen et al.,
stabilized compared to canonical nucleosomes (Tachiwana 2007).
et al., 2011).
Structural studies also revealed details on how proteins recog- Toward Structural Cell Biology
nize nucleosomes. A structure of a nucleosome in complex with In the coming years, X-ray crystallography will likely continue to
RCC1, a regulator of chromatin condensation, showed how this provide landmark structures that elucidate unknown mecha-
protein recognizes both histones and DNA to specifically bind nisms in chromatin and transcription biology. However, many
nucleosomes (Makde et al., 2010). Another nucleosome struc- proteins that function in chromatin and transcription are modular
ture in complex with the gene-silencing factor Sir3 indicated by design. To resolve the structure of flexible factors and tran-
how protein-nucleosome interactions are regulated by modifica- sient multicomponent complexes, crystallography will often be
tions in histone tails (Armache et al., 2011). integrated with complementary techniques. Of particular impor-
tance will be electron microscopy, which enables placement of
How Chromatin Marks Function crystal structures of complex components but can now also
Covalent histone modifications provide another layer of gene reach high resolution that enables building of atomic models
regulation (Strahl and Allis, 2000). Histone modifications include (Kühlbrandt, 2014; Wong et al., 2014). Crosslinking and mass
acetylation, methylation, phosphorylation, and ubiquitination spectrometry (Gingras et al., 2007; Serpa et al., 2012) will be
and can be associated with active transcription or repression. routinely used to derive the relative position of known structures
Enzymes that set or remove these marks are known as ‘‘writers’’ and to support models obtained by a combination of electron mi-
and ‘‘erasers,’’ respectively. The structure of the histone acetyl- croscopy and crystallography.
transferase Gcn5 provided insights into how chromatin marks A central future challenge will be the analysis of molecular
are written (Rojas et al., 1999) (Figure 1). The structure of a structures within their cellular context and of structural changes
portion of the acetyltransferase p300 explained mutations asso- in space and time. Advanced light microscopy techniques can
ciated with human cancers (Liu et al., 2008). The subunit orga- now resolve detailed structures of assemblies such as nuclear
nization of the large acetyltransferase complex NuA4 and its pore complexes (Szymborska et al., 2013) or the cytoskeleton
mode of interaction with the nucleosome were revealed by elec- (Xu et al., 2013). A combination of in vivo crosslinking with
tron microscopy (Chittuluru et al., 2011). Crystal structures of deep sequencing and computer simulations can elucidate the
histone methyltransferases revealed their mechanism and how overall folding of chromosomes (Naumova et al., 2013). Electron
specificity for histones was achieved (Kwon et al., 2003; Min tomography provides three-dimensional images of the nuclear
et al., 2002; Wilson et al., 2002; Xiao et al., 2003; Zhang et al., pore complex (Beck et al., 2004; Bui et al., 2013) or polysomes
2002). (Brandt et al., 2009).
Crystallography also showed how eraser enzymes work. The We are witnessing the advent of a new research field that may
structure of a bacterial homolog of a histone deacetylase (Finnin be referred to as structural cell biology. Structural biologists may
et al., 1999) was followed by structures of the NAD-dependent soon tackle most fundamental questions in biology. What is the
Sir2 enzyme (Avalos et al., 2002; Finnin et al., 2001; Min et al., conformational space for genomes, and how is it explored and
2001) and eukaryotic zinc-dependent histone deacetylases (So- utilized during gene activation and cell differentiation? What is
moza et al., 2004; Vannini et al., 2004). Histone demethylase the three-dimensional structure of genes and how does it change
structures of the LSD1 (Chen et al., 2006; Stavropoulos et al., during transcription? What is the dynamic architecture of tran-
2006; Yang et al., 2006) and JmJ (Ng et al., 2007) classes re- sient RNA assemblies with multiple proteins? Answers to these
vealed the basis for substrate specificity. The structure of the questions will require the development of new techniques and al-
four-subunit deubiquitination module of the SAGA complex pro- gorithms to bridge resolution gaps, to integrate structural data
vided the basis for substrate specificity and activation of this from multiple sources, and to embed structures into their biolog-
eraser (Köhler et al., 2010; Samara et al., 2010). ical context.
Histone marks can recruit proteins via specific ‘‘reader’’ do-
mains. The bromodomain binds acetylated lysine residues, as ACKNOWLEDGMENTS
observed for the factors P/CAF, Taf1, and Gcn5 (Dhalluin
I thank members of our laboratory and the following colleagues who provided
et al., 1999; Jacobson et al., 2000; Owen et al., 2000). The chro-
comments: David Allis, Karim-Jean Armache, Alan Cheung, Richard Ebright,
modomain binds methylated lysines, as exemplified by the HP1 Andreas Ladurner, Robert Landick, Karolin Luger, Ronen Marmorstein, Chris-
chromodomain bound to a histone H3 peptide methylated at toph Müller, Dinshaw Patel, Alessandro Vannini, and Cynthia Wolberger.
lysine-9 (Jacobs and Khorasanizadeh, 2002). The PHD finger I thank Lucas Farnung for help with preparing the figure.

Cell 159, November 20, 2014 ª2014 Elsevier Inc. 989

REFERENCES grated structural analysis of the human nuclear pore complex scaffold. Cell
155, 1233–1243.
Andel, F., 3rd, Ladurner, A.G., Inouye, C., Tjian, R., and Nogales, E. (1999). Bushnell, D.A., Westover, K.D., Davis, R.E., and Kornberg, R.D. (2004). Struc-
Three-dimensional structure of the human TFIID-IIA-IIB complex. Science tural basis of transcription: an RNA polymerase II-TFIIB cocrystal at 4.5 Ang-
286, 2153–2156. stroms. Science 303, 983–988.
Anderson, W.F., Ohlendorf, D.H., Takeda, Y., and Matthews, B.W. (1981). Campagne, S., Marsh, M.E., Capitani, G., Vorholt, J.A., and Allain, F.H. (2014).
Structure of the cro repressor from bacteriophage lambda and its interaction Structural basis for -10 promoter element melting by environmentally induced
with DNA. Nature 290, 754–758. sigma factors. Nat. Struct. Mol. Biol. 21, 269–276.
Anderson, J.E., Ptashne, M., and Harrison, S.C. (1987). Structure of the Chang, W.H., and Kornberg, R.D. (2000). Electron crystal structure of the tran-
repressor-operator complex of bacteriophage 434. Nature 326, 846–852. scription factor and DNA repair complex, core TFIIH. Cell 102, 609–613.
Arents, G., Burlingame, R.W., Wang, B.C., Love, W.E., and Moudrianakis, E.N. Cheetham, G.M., and Steitz, T.A. (1999). Structure of a transcribing T7 RNA
(1991). The nucleosomal core histone octamer at 3.1 A resolution: a tripartite polymerase initiation complex. Science 286, 2305–2309.
protein assembly and a left-handed superhelix. Proc. Natl. Acad. Sci. USA Cheetham, G.M., Jeruzalmi, D., and Steitz, T.A. (1999). Structural basis for
88, 10148–10152. initiation of transcription from an RNA polymerase-promoter complex. Nature
Armache, K.J., Garlick, J.D., Canzio, D., Narlikar, G.J., and Kingston, R.E. 399, 80–83.
(2011). Structural basis of silencing: Sir3 BAH domain in complex with a nucle- Chen, H.T., and Hahn, S. (2003). Binding of TFIIB to RNA polymerase II: Map-
osome at 3.0 Å resolution. Science 334, 977–982. ping the binding site for the TFIIB zinc ribbon domain within the preinitiation
Avalos, J.L., Celic, I., Muhammad, S., Cosgrove, M.S., Boeke, J.D., and complex. Mol. Cell 12, 437–447.
Wolberger, C. (2002). Structure of a Sir2 enzyme bound to an acetylated p53 Chen, Y., Yang, Y., Wang, F., Wan, K., Yamane, K., Zhang, Y., and Lei, M.
peptide. Mol. Cell 10, 523–535. (2006). Crystal structure of human histone lysine-specific demethylase 1
Basu, R.S., and Murakami, K.S. (2013). Watching the bacteriophage N4 RNA (LSD1). Proc. Natl. Acad. Sci. USA 103, 13956–13961.
polymerase transcription by time-dependent soak-trigger-freeze X-ray crys- Cheung, A.C., and Cramer, P. (2011). Structural basis of RNA polymerase II
tallography. J. Biol. Chem. 288, 3305–3311. backtracking, arrest and reactivation. Nature 471, 249–253.
Baumli, S., Lolli, G., Lowe, E.D., Troiani, S., Rusconi, L., Bullock, A.N., Debrec- Chittuluru, J.R., Chaban, Y., Monnet-Saksouk, J., Carrozza, M.J., Sapountzi,
zeni, J.E., Knapp, S., and Johnson, L.N. (2008). The structure of P-TEFb V., Selleck, W., Huang, J., Utley, R.T., Cramet, M., Allard, S., et al. (2011).
(CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphoryla- Structure and nucleosome interaction of the yeast NuA4 and Piccolo-NuA4
tion. EMBO J. 27, 1907–1918. histone acetyltransferase complexes. Nat. Struct. Mol. Biol. 18, 1196–1203.
Baumli, S., Hole, A.J., Wang, L.Z., Noble, M.E., and Endicott, J.A. (2012). The Cho, Y., Gorina, S., Jeffrey, P.D., and Pavletich, N.P. (1994). Crystal structure
CDK9 tail determines the reaction pathway of positive transcription elongation of a p53 tumor suppressor-DNA complex: understanding tumorigenic muta-
factor b. Structure 20, 1788–1795. tions. Science 265, 346–355.
Beck, M., Förster, F., Ecke, M., Plitzko, J.M., Melchior, F., Gerisch, G., Bau- Choo, Y., Sánchez-Garcı́a, I., and Klug, A. (1994). In vivo repression by a site-
meister, W., and Medalia, O. (2004). Nuclear pore complex structure and dy- specific DNA-binding protein designed against an oncogenic sequence. Na-
namics revealed by cryoelectron tomography. Science 306, 1387–1390. ture 372, 642–645.
Becker, S., Groner, B., and Müller, C.W. (1998). Three-dimensional structure of Cianfrocco, M.A., Kassavetis, G.A., Grob, P., Fang, J., Juven-Gershon, T., Ka-
the Stat3beta homodimer bound to DNA. Nature 394, 145–151. donaga, J.T., and Nogales, E. (2013). Human TFIID binds to core promoter
Bell, C.E., and Lewis, M. (2000). A closer view of the conformation of the Lac DNA in a reorganized structural state. Cell 152, 120–131.
repressor bound to operator. Nat. Struct. Biol. 7, 209–214. Clapier, C.R., and Cairns, B.R. (2012). Regulation of ISWI involves inhibitory
Benoff, B., Yang, H., Lawson, C.L., Parkinson, G., Liu, J., Blatter, E., Ebright, modules antagonized by nucleosomal epitopes. Nature 492, 280–284.
Y.W., Berman, H.M., and Ebright, R.H. (2002). Structural basis of transcription Clore, G.M., Omichinski, J.G., Sakaguchi, K., Zambrano, N., Sakamoto, H.,
activation: the CAP-alpha CTD-DNA complex. Science 297, 1562–1566. Appella, E., and Gronenborn, A.M. (1994). High-resolution structure of the olig-
Bieniossek, C., Papai, G., Schaffitzel, C., Garzoni, F., Chaillet, M., Scheer, E., omerization domain of p53 by multidimensional NMR. Science 265, 386–391.
Papadopoulos, P., Tora, L., Schultz, P., and Berger, I. (2013). The architec- Cramer, P., Bushnell, D.A., Fu, J., Gnatt, A.L., Maier-Davis, B., Thompson,
ture of human general transcription factor TFIID core complex. Nature 493, N.E., Burgess, R.R., Edwards, A.M., David, P.R., and Kornberg, R.D. (2000).
699–702. Architecture of RNA polymerase II and implications for the transcription mech-
Bösken, C.A., Farnung, L., Hintermair, C., Merzel Schachter, M., Vogel-Bach- anism. Science 288, 640–649.
mayr, K., Blazek, D., Anand, K., Fisher, R.P., Eick, D., and Geyer, M. (2014). Cramer, P., Bushnell, D.A., and Kornberg, R.D. (2001). Structural basis of
The structure and substrate specificity of human Cdk12/Cyclin K. Nat. Com- transcription: RNA polymerase II at 2.8 angstrom resolution. Science 292,
mun. 5, 3505. 1863–1876.
Brandt, F., Etchells, S.A., Ortiz, J.O., Elcock, A.H., Hartl, F.U., and Baumeis- Dhalluin, C., Carlson, J.E., Zeng, L., He, C., Aggarwal, A.K., and Zhou, M.M.
ter, W. (2009). The native 3D organization of bacterial polysomes. Cell 136, (1999). Structure and ligand of a histone acetyltransferase bromodomain.
261–271. Nature 399, 491–496.
Brzovic, P.S., Heikaus, C.C., Kisselev, L., Vernon, R., Herbig, E., Pacheco, Dürr, H., Körner, C., Müller, M., Hickmann, V., and Hopfner, K.P. (2005). X-ray
D., Warfield, L., Littlefield, P., Baker, D., Klevit, R.E., and Hahn, S. (2011). structures of the Sulfolobus solfataricus SWI2/SNF2 ATPase core and its com-
The acidic transcription activator Gcn4 binds the mediator subunit Gal11/ plex with DNA. Cell 121, 363–373.
Med15 using a simple protein interface forming a fuzzy complex. Mol. Cell Ellenberger, T.E., Brandl, C.J., Struhl, K., and Harrison, S.C. (1992). The GCN4
44, 942–953. basic region leucine zipper binds DNA as a dimer of uninterrupted alpha heli-
Brzozowski, A.M., Pike, A.C., Dauter, Z., Hubbard, R.E., Bonn, T., Engström, ces: crystal structure of the protein-DNA complex. Cell 71, 1223–1237.
O., Ohman, L., Greene, G.L., Gustafsson, J.A., and Carlquist, M. (1997). Mo- Elsässer, S.J., Huang, H., Lewis, P.W., Chin, J.W., Allis, C.D., and Patel, D.J.
lecular basis of agonism and antagonism in the oestrogen receptor. Nature (2012). DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition.
389, 753–758. Nature 491, 560–565.
Bui, K.H., von Appen, A., DiGuilio, A.L., Ori, A., Sparks, L., Mackmull, M.T., Engel, C., Sainsbury, S., Cheung, A.C., Kostrewa, D., and Cramer, P. (2013).
Bock, T., Hagen, W., Andrés-Pons, A., Glavy, J.S., and Beck, M. (2013). Inte- RNA polymerase I structure and transcription regulation. Nature 502, 650–655.

990 Cell 159, November 20, 2014 ª2014 Elsevier Inc.

English, C.M., Adkins, M.W., Carson, J.J., Churchill, M.E., and Tyler, J.K. Huxford, T., Huang, D.B., Malek, S., and Ghosh, G. (1998). The crystal struc-
(2006). Structural basis for the histone chaperone activity of Asf1. Cell 127, ture of the IkappaBalpha/NF-kappaB complex reveals mechanisms of
495–508. NF-kappaB inactivation. Cell 95, 759–770.
Fabrega, C., Shen, V., Shuman, S., and Lima, C.D. (2003). Structure of an Imasaki, T., Calero, G., Cai, G., Tsai, K.L., Yamada, K., Cardelli, F., Erdjument-
mRNA capping enzyme bound to the phosphorylated carboxy-terminal Bromage, H., Tempst, P., Berger, I., Kornberg, G.L., et al. (2011). Architecture
domain of RNA polymerase II. Mol. Cell 11, 1549–1561. of the Mediator head module. Nature 475, 240–243.
Fairall, L., Schwabe, J.W., Chapman, L., Finch, J.T., and Rhodes, D. (1993). Jacobs, S.A., and Khorasanizadeh, S. (2002). Structure of HP1 chromodomain
The crystal structure of a two zinc-finger peptide reveals an extension to the bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083.
rules for zinc-finger/DNA recognition. Nature 366, 483–487. Jacobson, R.H., Ladurner, A.G., King, D.S., and Tjian, R. (2000). Structure and
Fan, L., Arvai, A.S., Cooper, P.K., Iwai, S., Hanaoka, F., and Tainer, J.A. (2006). function of a human TAFII250 double bromodomain module. Science 288,
Conserved XPB core structure and motifs for DNA unwinding: implications for 1422–1425.
pathway selection of transcription or excision repair. Mol. Cell 22, 27–37. Jain, D., Nickels, B.E., Sun, L., Hochschild, A., and Darst, S.A. (2004). Structure
Feklistov, A., and Darst, S.A. (2011). Structural basis for promoter-10 element of a ternary transcription activation complex. Mol. Cell 13, 45–53.
recognition by the bacterial RNA polymerase s subunit. Cell 147, 1257–1269. Jeruzalmi, D., and Steitz, T.A. (1998). Structure of T7 RNA polymerase com-
Fernández-Tornero, C., Moreno-Morcillo, M., Rashid, U.J., Taylor, N.M., Ruiz, plexed to the transcriptional inhibitor T7 lysozyme. EMBO J. 17, 4101–4113.
F.M., Gruene, T., Legrand, P., Steuerwald, U., and Müller, C.W. (2013). Crystal Jordan, S.R., and Pabo, C.O. (1988). Structure of the lambda complex at 2.5
structure of the 14-subunit RNA polymerase I. Nature 502, 644–649. A resolution: details of the repressor-operator interactions. Science 242,
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W.B., Fedorov, O., 893–899.
Morse, E.M., Keates, T., Hickman, T.T., Felletar, I., et al. (2010). Selective inhi- Kamenski, T., Heilmeier, S., Meinhart, A., and Cramer, P. (2004). Structure and
bition of BET bromodomains. Nature 468, 1067–1073. mechanism of RNA polymerase II CTD phosphatases. Mol. Cell 15, 399–407.
Finnin, M.S., Donigian, J.R., Cohen, A., Richon, V.M., Rifkind, R.A., Marks, Kettenberger, H., Armache, K.J., and Cramer, P. (2003). Architecture of the
P.A., Breslow, R., and Pavletich, N.P. (1999). Structures of a histone deacety- RNA polymerase II-TFIIS complex and implications for mRNA cleavage. Cell
lase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193. 114, 347–357.

Finnin, M.S., Donigian, J.R., and Pavletich, N.P. (2001). Structure of the histone Kim, J.L., Nikolov, D.B., and Burley, S.K. (1993a). Co-crystal structure of TBP
deacetylase SIRT2. Nat. Struct. Biol. 8, 621–625. recognizing the minor groove of a TATA element. Nature 365, 520–527.

Friedman, A.M., Fischmann, T.O., and Steitz, T.A. (1995). Crystal structure of Kim, Y., Geiger, J.H., Hahn, S., and Sigler, P.B. (1993b). Crystal structure of a
lac repressor core tetramer and its implications for DNA looping. Science 268, yeast TBP/TATA-box complex. Nature 365, 512–520.
1721–1727. Kissinger, C.R., Liu, B.S., Martin-Blanco, E., Kornberg, T.B., and Pabo, C.O.
Geiger, J.H., Hahn, S., Lee, S., and Sigler, P.B. (1996). Crystal structure of the (1990). Crystal structure of an engrailed homeodomain-DNA complex at 2.8
yeast TFIIA/TBP/DNA complex. Science 272, 830–836. A resolution: a framework for understanding homeodomain-DNA interactions.
Cell 63, 579–590.
Ghosh, G., van Duyne, G., Ghosh, S., and Sigler, P.B. (1995). Structure of
Klimasauskas, S., Kumar, S., Roberts, R.J., and Cheng, X. (1994). HhaI meth-
NF-kappa B p50 homodimer bound to a kappa B site. Nature 373, 303–310.
yltransferase flips its target base out of the DNA helix. Cell 76, 357–369.
Ghosh, A., Shuman, S., and Lima, C.D. (2008). The structure of Fcp1, an
Köhler, A., Zimmerman, E., Schneider, M., Hurt, E., and Zheng, N. (2010).
essential RNA polymerase II CTD phosphatase. Mol. Cell 32, 478–490.
Structural basis for assembly and activation of the heterotetrameric SAGA his-
Gibbons, B.J., Brignole, E.J., Azubel, M., Murakami, K., Voss, N.R., Bushnell, tone H2B deubiquitinase module. Cell 141, 606–617.
D.A., Asturias, F.J., and Kornberg, R.D. (2012). Subunit architecture of general
König, P., and Richmond, T.J. (1993). The X-ray structure of the GCN4-bZIP
transcription factor TFIIH. Proc. Natl. Acad. Sci. USA 109, 1949–1954.
bound to ATF/CREB site DNA shows the complex depends on DNA flexibility.
Gingras, A.C., Gstaiger, M., Raught, B., and Aebersold, R. (2007). Analysis J. Mol. Biol. 233, 139–154.
of protein complexes using mass spectrometry. Nat. Rev. Mol. Cell Biol. 8,
Korkhin, Y., Unligil, U.M., Littlefield, O., Nelson, P.J., Stuart, D.I., Sigler, P.B.,
645–654.
Bell, S.D., and Abrescia, N.G. (2009). Evolution of complex RNA polymerases:
Gnatt, A.L., Cramer, P., Fu, J., Bushnell, D.A., and Kornberg, R.D. (2001). the complete archaeal RNA polymerase structure. PLoS Biol. 7, e1000102.
Structural basis of transcription: an RNA polymerase II elongation complex Kostrewa, D., Zeller, M.E., Armache, K.J., Seizl, M., Leike, K., Thomm, M., and
at 3.3 A resolution. Science 292, 1876–1882. Cramer, P. (2009). RNA polymerase II-TFIIB structure and mechanism of tran-
Grünberg, S., Warfield, L., and Hahn, S. (2012). Architecture of the RNA poly- scription initiation. Nature 462, 323–330.
merase II preinitiation complex and mechanism of ATP-dependent promoter Kühlbrandt, W. (2014). Biochemistry. The resolution revolution. Science 343,
opening. Nat. Struct. Mol. Biol. 19, 788–796. 1443–1444.
Hauk, G., McKnight, J.N., Nodelman, I.M., and Bowman, G.D. (2010). The Kussie, P.H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A.J.,
chromodomains of the Chd1 chromatin remodeler regulate DNA access to and Pavletich, N.P. (1996). Structure of the MDM2 oncoprotein bound to the
the ATPase motor. Mol. Cell 39, 711–723. p53 tumor suppressor transactivation domain. Science 274, 948–953.
He, Y., Fang, J., Taatjes, D.J., and Nogales, E. (2013). Structural visualization Kwon, T., Chang, J.H., Kwak, E., Lee, C.W., Joachimiak, A., Kim, Y.C., Lee, J.,
of key steps in human transcription initiation. Nature 495, 481–486. and Cho, Y. (2003). Mechanism of histone lysine methyl transfer revealed by
Hirata, A., Klein, B.J., and Murakami, K.S. (2008). The X-ray crystal structure of the structure of SET7/9-AdoMet. EMBO J. 22, 292–303.
RNA polymerase from Archaea. Nature 451, 851–854. Larivière, L., Plaschka, C., Seizl, M., Wenzeck, L., Kurth, F., and Cramer, P.
Hondele, M., Stuwe, T., Hassler, M., Halbach, F., Bowman, A., Zhang, E.T., Nij- (2012). Structure of the Mediator head module. Nature 492, 448–451.
meijer, B., Kotthoff, C., Rybin, V., Amlacher, S., et al. (2013). Structural basis of Lesser, D.R., Kurpiewski, M.R., and Jen-Jacobson, L. (1990). The energetic
histone H2A-H2B recognition by the essential chaperone FACT. Nature 499, basis of specificity in the Eco RI endonuclease—DNA interaction. Science
111–114. 250, 776–786.
Hu, H., Liu, Y., Wang, M., Fang, J., Huang, H., Yang, N., Li, Y., Wang, J., Yao, Leurent, C., Sanders, S., Ruhlmann, C., Mallouh, V., Weil, P.A., Kirschner,
X., Shi, Y., et al. (2011). Structure of a CENP-A-histone H4 heterodimer in com- D.B., Tora, L., and Schultz, P. (2002). Mapping histone fold TAFs within yeast
plex with chaperone HJURP. Genes Dev. 25, 901–906. TFIID. EMBO J. 21, 3424–3433.

Cell 159, November 20, 2014 ª2014 Elsevier Inc. 991

Lewis, M., Chang, G., Horton, N.C., Kercher, M.A., Pace, H.C., Schumacher, Murakami, K., Elmlund, H., Kalisman, N., Bushnell, D.A., Adams, C.M., Azubel,
M.A., Brennan, R.G., and Lu, P. (1996). Crystal structure of the lactose operon M., Elmlund, D., Levi-Kalisman, Y., Liu, X., Gibbons, B.J., et al. (2013). Archi-
repressor and its complexes with DNA and inducer. Science 271, 1247–1254. tecture of an RNA polymerase II transcription pre-initiation complex. Science
Li, T., Stark, M.R., Johnson, A.D., and Wolberger, C. (1995). Crystal structure 342, 1238724.
of the MATa1/MAT alpha 2 homeodomain heterodimer bound to DNA. Science Naumova, N., Imakaev, M., Fudenberg, G., Zhan, Y., Lajoie, B.R., Mirny, L.A.,
270, 262–269. and Dekker, J. (2013). Organization of the mitotic chromosome. Science 342,
948–953.
Li, H., Ilin, S., Wang, W., Duncan, E.M., Wysocka, J., Allis, C.D., and Patel, D.J.
(2006). Molecular basis for site-specific read-out of histone H3K4me3 by the Ng, S.S., Kavanagh, K.L., McDonough, M.A., Butler, D., Pilka, E.S., Lienard,
BPTF PHD finger of NURF. Nature 442, 91–95. B.M., Bray, J.E., Savitsky, P., Gileadi, O., von Delft, F., et al. (2007). Crystal
structures of histone demethylase JMJD2A reveal basis for substrate speci-
Liu, X., Wang, L., Zhao, K., Thompson, P.R., Hwang, Y., Marmorstein, R., and
ficity. Nature 448, 87–91.
Cole, P.A. (2008). The structural basis of protein acetylation by the p300/CBP
transcriptional coactivator. Nature 451, 846–850. Ngo, H.B., Kaiser, J.T., and Chan, D.C. (2011). The mitochondrial transcription
and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat.
Liu, X., Bushnell, D.A., Wang, D., Calero, G., and Kornberg, R.D. (2010). Struc-
Struct. Mol. Biol. 18, 1290–1296.
ture of an RNA polymerase II-TFIIB complex and the transcription initiation
mechanism. Science 327, 206–209. Nguyen, V.Q., Ranjan, A., Stengel, F., Wei, D., Aebersold, R., Wu, C., and
Leschziner, A.E. (2013). Molecular architecture of the ATP-dependent chro-
Lolli, G., Lowe, E.D., Brown, N.R., and Johnson, L.N. (2004). The crystal struc- matin-remodeling complex SWR1. Cell 154, 1220–1231.
ture of human CDK7 and its protein recognition properties. Structure 12, 2067–
Nikolov, D.B., Hu, S.H., Lin, J., Gasch, A., Hoffmann, A., Horikoshi, M., Chua,
2079.
N.H., Roeder, R.G., and Burley, S.K. (1992). Crystal structure of TFIID TATA-
Luger, K., Mäder, A.W., Richmond, R.K., Sargent, D.F., and Richmond, T.J. box binding protein. Nature 360, 40–46.
(1997). Crystal structure of the nucleosome core particle at 2.8 A resolution.
Nikolov, D.B., Chen, H., Halay, E.D., Usheva, A.A., Hisatake, K., Lee, D.K.,
Nature 389, 251–260.
Roeder, R.G., and Burley, S.K. (1995). Crystal structure of a TFIIB-TBP-
Luisi, B.F., Xu, W.X., Otwinowski, Z., Freedman, L.P., Yamamoto, K.R., and Si- TATA-element ternary complex. Nature 377, 119–128.
gler, P.B. (1991). Crystallographic analysis of the interaction of the glucocorti-
Obri, A., Ouararhni, K., Papin, C., Diebold, M.L., Padmanabhan, K., Marek, M.,
coid receptor with DNA. Nature 352, 497–505.
Stoll, I., Roy, L., Reilly, P.T., Mak, T.W., et al. (2014). ANP32E is a histone chap-
Makde, R.D., England, J.R., Yennawar, H.P., and Tan, S. (2010). Structure of erone that removes H2A.Z from chromatin. Nature 505, 648–653.
RCC1 chromatin factor bound to the nucleosome core particle. Nature 467, Opalka, N., Chlenov, M., Chacon, P., Rice, W.J., Wriggers, W., and Darst, S.A.
562–566. (2003). Structure and function of the transcription elongation factor GreB
Malhotra, A., Severinova, E., and Darst, S.A. (1996). Crystal structure of a bound to bacterial RNA polymerase. Cell 114, 335–345.
sigma 70 subunit fragment from E. coli RNA polymerase. Cell 87, 127–136. Otting, G., Qian, Y.Q., Billeter, M., Müller, M., Affolter, M., Gehring, W.J., and
Marmorstein, R., Carey, M., Ptashne, M., and Harrison, S.C. (1992). DNA Wüthrich, K. (1990). Protein—DNA contacts in the structure of a homeodo-
recognition by GAL4: structure of a protein-DNA complex. Nature 356, main—DNA complex determined by nuclear magnetic resonance spectros-
408–414. copy in solution. EMBO J. 9, 3085–3092.
McKay, D.B., and Steitz, T.A. (1981). Structure of catabolite gene activator Otwinowski, Z., Schevitz, R.W., Zhang, R.G., Lawson, C.L., Joachimiak, A.,
protein at 2.9 A resolution suggests binding to left-handed B-DNA. Nature Marmorstein, R.Q., Luisi, B.F., and Sigler, P.B. (1988). Crystal structure of
290, 744–749. trp repressor/operator complex at atomic resolution. Nature 335, 321–329.

Meinhart, A., and Cramer, P. (2004). Recognition of RNA polymerase II car- Owen, D.J., Ornaghi, P., Yang, J.C., Lowe, N., Evans, P.R., Ballario, P., Neu-
boxy-terminal domain by 30 -RNA-processing factors. Nature 430, 223–226. haus, D., Filetici, P., and Travers, A.A. (2000). The structural basis for the
recognition of acetylated histone H4 by the bromodomain of histone acetyl-
Meyer, K.D., Lin, S.C., Bernecky, C., Gao, Y., and Taatjes, D.J. (2010). p53 ac-
transferase gcn5p. EMBO J. 19, 6141–6149.
tivates transcription by directing structural shifts in Mediator. Nat. Struct. Mol.
Pabo, C.O., and Lewis, M. (1982). The operator-binding domain of lambda
Biol. 17, 753–760.
repressor: structure and DNA recognition. Nature 298, 443–447.
Min, J., Landry, J., Sternglanz, R., and Xu, R.M. (2001). Crystal structure of a
Panne, D., Maniatis, T., and Harrison, S.C. (2007). An atomic model of the inter-
SIR2 homolog-NAD complex. Cell 105, 269–279.
feron-beta enhanceosome. Cell 129, 1111–1123.
Min, J., Zhang, X., Cheng, X., Grewal, S.I., and Xu, R.M. (2002). Structure of
Park, Y.J., and Luger, K. (2006). The structure of nucleosome assembly protein
the SET domain histone lysine methyltransferase Clr4. Nat. Struct. Biol. 9,
1. Proc. Natl. Acad. Sci. USA 103, 1248–1253.
828–832.
Pavletich, N.P., and Pabo, C.O. (1991). Zinc finger-DNA recognition: crystal
Morinière, J., Rousseaux, S., Steuerwald, U., Soler-López, M., Curtet, S., Vitte, structure of a Zif268-DNA complex at 2.1 A. Science 252, 809–817.
A.L., Govin, J., Gaucher, J., Sadoul, K., Hart, D.J., et al. (2009). Cooperative
Peña, P.V., Davrazou, F., Shi, X., Walter, K.L., Verkhusha, V.V., Gozani, O.,
binding of two acetylation marks on a histone tail by a single bromodomain.
Zhao, R., and Kutateladze, T.G. (2006). Molecular mechanism of histone
Nature 461, 664–668.
H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103.
Mühlbacher, W., Sainsbury, S., Hemann, M., Hantsche, M., Neyer, S., Herzog,
Piper, D.E., Batchelor, A.H., Chang, C.P., Cleary, M.L., and Wolberger, C.
F., and Cramer, P. (2014). Conserved architecture of the core RNA polymerase
(1999). Structure of a HoxB1-Pbx1 heterodimer bound to DNA: role of the
II initiation complex. Nat. Commun. 5, 4310.
hexapeptide and a fourth homeodomain helix in complex formation. Cell 96,
Müller, C.W., Rey, F.A., Sodeoka, M., Verdine, G.L., and Harrison, S.C. 587–597.
(1995). Structure of the NF-kappa B p50 homodimer bound to DNA. Nature
Qian, Y.Q., Billeter, M., Otting, G., Müller, M., Gehring, W.J., and Wüthrich, K.
373, 311–317.
(1989). The structure of the Antennapedia homeodomain determined by NMR
Murakami, K.S., Masuda, S., Campbell, E.A., Muzzin, O., and Darst, S.A. spectroscopy in solution: comparison with prokaryotic repressors. Cell 59,
(2002a). Structural basis of transcription initiation: an RNA polymerase holoen- 573–580.
zyme-DNA complex. Science 296, 1285–1290. Racki, L.R., Naber, N., Pate, E., Leonard, J.D., Cooke, R., and Narlikar, G.J.
Murakami, K.S., Masuda, S., and Darst, S.A. (2002b). Structural basis of tran- (2014). The histone H4 tail regulates the conformation of the ATP-binding
scription initiation: RNA polymerase holoenzyme at 4 A resolution. Science pocket in the SNF2h chromatin remodeling enzyme. J. Mol. Biol. 426, 2034–
296, 1280–1284. 2044.

992 Cell 159, November 20, 2014 ª2014 Elsevier Inc.

Radhakrishnan, I., Pérez-Alvarado, G.C., Parker, D., Dyson, H.J., Montminy, Schwabe, J.W., Chapman, L., Finch, J.T., and Rhodes, D. (1993). The crystal
M.R., and Wright, P.E. (1997). Solution structure of the KIX domain of CBP structure of the estrogen receptor DNA-binding domain bound to DNA: how
bound to the transactivation domain of CREB: a model for activator:coactiva- receptors discriminate between their response elements. Cell 75, 567–578.
tor interactions. Cell 91, 741–752. Schwinghammer, K., Cheung, A.C., Morozov, Y.I., Agaronyan, K., Temiakov,
Reményi, A., Lins, K., Nissen, L.J., Reinbold, R., Schöler, H.R., and Wilmanns, D., and Cramer, P. (2013). Structure of human mitochondrial RNA polymerase
M. (2003). Crystal structure of a POU/HMG/DNA ternary complex suggests dif- elongation complex. Nat. Struct. Mol. Biol. 20, 1298–1303.
ferential assembly of Oct4 and Sox2 on two enhancers. Genes Dev. 17, 2048– Serpa, J.J., Parker, C.E., Petrotchenko, E.V., Han, J., Pan, J., and Borchers,
2059. C.H. (2012). Mass spectrometry-based structural proteomics. Eur. J. Mass
Rice, P.A., Yang, S., Mizuuchi, K., and Nash, H.A. (1996). Crystal structure of Spectrom. (Chichester, Eng.) 18, 251–267.
an IHF-DNA complex: a protein-induced DNA U-turn. Cell 87, 1295–1306. Shakked, Z., Rabinovich, D., Cruse, W.B., Egert, E., Kennard, O., Sala, G., Sal-
Richmond, T.J., Finch, J.T., Rushton, B., Rhodes, D., and Klug, A. (1984). isbury, S.A., and Viswamitra, M.A. (1981). Crystalline A-dna: the X-ray analysis
Structure of the nucleosome core particle at 7 A resolution. Nature 311, of the fragment d(G-G-T-A-T-A-C-C). Proc. R. Soc. Lond. B Biol. Sci. 213,
532–537. 479–487.
Ringel, R., Sologub, M., Morozov, Y.I., Litonin, D., Cramer, P., and Temiakov, Shi, Y. (2014). A glimpse of structural biology through X-ray crystallography.
D. (2011). Structure of human mitochondrial RNA polymerase. Nature 478, Cell 159, this issue, 995–1014.
269–273. Shiau, A.K., Barstad, D., Loria, P.M., Cheng, L., Kushner, P.J., Agard, D.A., and
Robertus, J.D., Ladner, J.E., Finch, J.T., Rhodes, D., Brown, R.S., Clark, B.F., Greene, G.L. (1998). The structural basis of estrogen receptor/coactivator
and Klug, A. (1974). Structure of yeast phenylalanine tRNA at 3 A resolution. recognition and the antagonism of this interaction by tamoxifen. Cell 95,
Nature 250, 546–551. 927–937.
Robinson, P.J., Fairall, L., Huynh, V.A., and Rhodes, D. (2006). EM measure- Somoza, J.R., Skene, R.J., Katz, B.A., Mol, C., Ho, J.D., Jennings, A.J., Luong,
ments define the dimensions of the ‘‘30-nm’’ chromatin fiber: evidence for a C., Arvai, A., Buggy, J.J., Chi, E., et al. (2004). Structural snapshots of human
compact, interdigitated structure. Proc. Natl. Acad. Sci. USA 103, 6506–6511. HDAC8 provide insights into the class I histone deacetylases. Structure 12,
Robinson, P.J., Bushnell, D.A., Trnka, M.J., Burlingame, A.L., and Kornberg, 1325–1334.
R.D. (2012). Structure of the mediator head module bound to the carboxy-ter- Song, J., Rechkoblit, O., Bestor, T.H., and Patel, D.J. (2011). Structure of
minal domain of RNA polymerase II. Proc. Natl. Acad. Sci. USA 109, 17931– DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA
17935. methylation. Science 331, 1036–1040.
Rojas, J.R., Trievel, R.C., Zhou, J., Mo, Y., Li, X., Berger, S.L., Allis, C.D., and Song, J., Teplova, M., Ishibe-Murakami, S., and Patel, D.J. (2012). Structure-
Marmorstein, R. (1999). Structure of Tetrahymena GCN5 bound to coenzyme based mechanistic insights into DNMT1-mediated maintenance DNA methyl-
A and a histone H3 peptide. Nature 401, 93–98. ation. Science 335, 709–712.
Rubio-Cosials, A., Sidow, J.F., Jiménez-Menéndez, N., Fernández-Millán, P., Song, F., Chen, P., Sun, D., Wang, M., Dong, L., Liang, D., Xu, R.M., Zhu, P.,
Montoya, J., Jacobs, H.T., Coll, M., Bernadó, P., and Solà, M. (2011). Human and Li, G. (2014). Cryo-EM study of the chromatin fiber reveals a double helix
mitochondrial transcription factor A induces a U-turn structure in the light twisted by tetranucleosomal units. Science 344, 376–380.
strand promoter. Nat. Struct. Mol. Biol. 18, 1281–1289. Sousa, R., Chung, Y.J., Rose, J.P., and Wang, B.C. (1993). Crystal structure of
Sainsbury, S., Niesser, J., and Cramer, P. (2013). Structure and function of the bacteriophage T7 RNA polymerase at 3.3 A resolution. Nature 364, 593–599.
initially transcribing RNA polymerase II-TFIIB complex. Nature 493, 437–440. Stavropoulos, P., Blobel, G., and Hoelz, A. (2006). Crystal structure and
Samara, N.L., Datta, A.B., Berndsen, C.E., Zhang, X., Yao, T., Cohen, R.E., and mechanism of human lysine-specific demethylase-1. Nat. Struct. Mol. Biol.
Wolberger, C. (2010). Structural insights into the assembly and function of the 13, 626–632.
SAGA deubiquitinating module. Science 328, 1025–1029. Steitz, T.A., and Steitz, J.A. (1993). A general two-metal-ion mechanism for
Saravanan, M., Wuerges, J., Bose, D., McCormack, E.A., Cook, N.J., Zhang, catalytic RNA. Proc. Natl. Acad. Sci. USA 90, 6498–6502.
X., and Wigley, D.B. (2012). Interactions between the nucleosome histone Strahl, B.D., and Allis, C.D. (2000). The language of covalent histone modifica-
core and Arp8 in the INO80 chromatin remodeling complex. Proc. Natl. tions. Nature 403, 41–45.
Acad. Sci. USA 109, 20883–20888. Suto, R.K., Clarkson, M.J., Tremethick, D.J., and Luger, K. (2000). Crystal
Schalch, T., Duda, S., Sargent, D.F., and Richmond, T.J. (2005). X-ray struc- structure of a nucleosome core particle containing the variant histone
ture of a tetranucleosome and its implications for the chromatin fibre. Nature H2A.Z. Nat. Struct. Biol. 7, 1121–1124.
436, 138–141. Szymborska, A., de Marco, A., Daigle, N., Cordes, V.C., Briggs, J.A., and Ellen-
Scheffer, M.P., Eltsov, M., and Frangakis, A.S. (2011). Evidence for short- berg, J. (2013). Nuclear pore scaffold structure analyzed by super-resolution
range helical order in the 30-nm chromatin fibers of erythrocyte nuclei. Proc. microscopy and particle averaging. Science 341, 655–658.
Natl. Acad. Sci. USA 108, 16992–16997. Taatjes, D.J., Näär, A.M., Andel, F., 3rd, Nogales, E., and Tjian, R. (2002).
Schevitz, R.W., Otwinowski, Z., Joachimiak, A., Lawson, C.L., and Sigler, P.B. Structure, function, and activator-induced conformations of the CRSP coacti-
(1985). The three-dimensional structure of trp repressor. Nature 317, 782–786. vator. Science 295, 1058–1062.
Schneider, E.V., Böttcher, J., Blaesse, M., Neumann, L., Huber, R., and Mas- Tachiwana, H., Kagawa, W., Shiga, T., Osakabe, A., Miya, Y., Saito, K., Hay-
kos, K. (2011). The structure of CDK8/CycC implicates specificity in the CDK/ ashi-Takanaka, Y., Oda, T., Sato, M., Park, S.Y., et al. (2011). Crystal struc-
cyclin family and reveals interaction with a deep pocket binder. J. Mol. Biol. ture of the human centromeric nucleosome containing CENP-A. Nature 476,
412, 251–266. 232–235.
Schuetz, A., Nana, D., Rose, C., Zocher, G., Milanovic, M., Koenigsmann, J., Tahirov, T.H., Temiakov, D., Anikin, M., Patlan, V., McAllister, W.T., Vassylyev,
Blasig, R., Heinemann, U., and Carstanjen, D. (2011). The structure of the D.G., and Yokoyama, S. (2002). Structure of a T7 RNA polymerase elongation
Klf4 DNA-binding domain links to self-renewal and macrophage differentia- complex at 2.9 A resolution. Nature 420, 43–50.
tion. Cell. Mol. Life Sci. 68, 3121–3131. Tahirov, T.H., Babayeva, N.D., Varzavand, K., Cooper, J.J., Sedore, S.C., and
Schultz, S.C., Shields, G.C., and Steitz, T.A. (1991). Crystal structure of a CAP- Price, D.H. (2010). Crystal structure of HIV-1 Tat complexed with human P-
DNA complex: the DNA is bent by 90 degrees. Science 253, 1001–1007. TEFb. Nature 465, 747–751.
Schultz, P., Fribourg, S., Poterszman, A., Mallouh, V., Moras, D., and Egly, J.M. Tan, S., and Richmond, T.J. (1998). Crystal structure of the yeast MATalpha2/
(2000). Molecular structure of human TFIIH. Cell 102, 599–607. MCM1/DNA ternary complex. Nature 391, 660–666.

Cell 159, November 20, 2014 ª2014 Elsevier Inc. 993

Tan, S., Hunziker, Y., Sargent, D.F., and Richmond, T.J. (1996). Crystal struc- Watson, J.D., and Crick, F.H. (1953). Molecular structure of nucleic acids; a
ture of a yeast TFIIA/TBP/DNA complex. Nature 381, 127–151. structure for deoxyribose nucleic acid. Nature 171, 737–738.
Temiakov, D., Patlan, V., Anikin, M., McAllister, W.T., Yokoyama, S., and Vas- Wilson, J.R., Jing, C., Walker, P.A., Martin, S.R., Howell, S.A., Blackburn,
sylyev, D.G. (2004). Structural basis for substrate selection by t7 RNA polymer- G.M., Gamblin, S.J., and Xiao, B. (2002). Crystal structure and functional anal-
ase. Cell 116, 381–391. ysis of the histone methyltransferase SET7/9. Cell 111, 105–115.
Thomä, N.H., Czyzewski, B.K., Alexeev, A.A., Mazin, A.V., Kowalczykowski, Wing, R., Drew, H., Takano, T., Broka, C., Tanaka, S., Itakura, K., and Dicker-
S.C., and Pavletich, N.P. (2005). Structure of the SWI2/SNF2 chromatin-re- son, R.E. (1980). Crystal structure analysis of a complete turn of B-DNA. Na-
modeling domain of eukaryotic Rad54. Nat. Struct. Mol. Biol. 12, 350–356. ture 287, 755–758.

Tosi, A., Haas, C., Herzog, F., Gilmozzi, A., Berninghausen, O., Ungewickell, Wolberger, C., Dong, Y.C., Ptashne, M., and Harrison, S.C. (1988). Structure of
C., Gerhold, C.B., Lakomek, K., Aebersold, R., Beckmann, R., and Hopfner, a phage 434 Cro/DNA complex. Nature 335, 789–795.
K.P. (2013). Structure and subunit topology of the INO80 chromatin remodeler Wong, W., Bai, X.C., Brown, A., Fernandez, I.S., Hanssen, E., Condron, M.,
and its nucleosome complex. Cell 154, 1207–1219. Tan, Y.H., Baum, J., and Scheres, S.H. (2014). Cryo-EM structure of the Plas-
modium falciparum 80S ribosome bound to the anti-protozoan drug emetine.
Tsai, W.W., Wang, Z., Yiu, T.T., Akdemir, K.C., Xia, W., Winter, S., Tsai, C.Y.,
eLife 3, e03080.
Shi, X., Schwarzer, D., Plunkett, W., et al. (2010). TRIM24 links a non-canonical
histone signature to breast cancer. Nature 468, 927–932. Xi, Q., Wang, Z., Zaromytidou, A.I., Zhang, X.H., Chow-Tsang, L.F., Liu, J.X.,
Kim, H., Barlas, A., Manova-Todorova, K., Kaartinen, V., et al. (2011). A poised
Tsai, K.L., Tomomori-Sato, C., Sato, S., Conaway, R.C., Conaway, J.W., and
chromatin platform for TGF-b access to master regulators. Cell 147, 1511–
Asturias, F.J. (2014). Subunit architecture and functional modular rearrange-
1524.
ments of the transcriptional mediator complex. Cell 157, 1430–1444.
Xiang, K., Nagaike, T., Xiang, S., Kilic, T., Beh, M.M., Manley, J.L., and Tong, L.
Vannini, A., Volpari, C., Filocamo, G., Casavola, E.C., Brunetti, M., Renzoni, D.,
(2010). Crystal structure of the human symplekin-Ssu72-CTD phosphopeptide
Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., et al. (2004). Crystal
complex. Nature 467, 729–733.
structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8,
complexed with a hydroxamic acid inhibitor. Proc. Natl. Acad. Sci. USA 101, Xiao, B., Jing, C., Wilson, J.R., Walker, P.A., Vasisht, N., Kelly, G., Howell, S.,
15064–15069. Taylor, I.A., Blackburn, G.M., and Gamblin, S.J. (2003). Structure and cata-
lytic mechanism of the human histone methyltransferase SET7/9. Nature
Vassylyev, D.G., Sekine, S., Laptenko, O., Lee, J., Vassylyeva, M.N., Boru- 421, 652–656.
khov, S., and Yokoyama, S. (2002). Crystal structure of a bacterial RNA poly-
Xu, K., Zhong, G., and Zhuang, X. (2013). Actin, spectrin, and associated pro-
merase holoenzyme at 2.6 A resolution. Nature 417, 712–719.
teins form a periodic cytoskeletal structure in axons. Science 339, 452–456.
Vassylyev, D.G., Vassylyeva, M.N., Zhang, J., Palangat, M., Artsimovitch, I.,
Yamada, K., Frouws, T.D., Angst, B., Fitzgerald, D.J., DeLuca, C., Schimmele,
and Landick, R. (2007). Structural basis for substrate loading in bacterial
K., Sargent, D.F., and Richmond, T.J. (2011). Structure and mechanism of the
RNA polymerase. Nature 448, 163–168.
chromatin remodelling factor ISW1a. Nature 472, 448–453.
Verdecia, M.A., Bowman, M.E., Lu, K.P., Hunter, T., and Noel, J.P. (2000).
Yang, M., Gocke, C.B., Luo, X., Borek, D., Tomchick, D.R., Machius, M., Otwi-
Structural basis for phosphoserine-proline recognition by group IV WW do-
nowski, Z., and Yu, H. (2006). Structural basis for CoREST-dependent deme-
mains. Nat. Struct. Biol. 7, 639–643.
thylation of nucleosomes by the human LSD1 histone demethylase. Mol. Cell
Vermeulen, M., Mulder, K.W., Denissov, S., Pijnappel, W.W., van Schaik, F.M., 23, 377–387.
Varier, R.A., Baltissen, M.P., Stunnenberg, H.G., Mann, M., and Timmers, H.T. Yin, Y.W., and Steitz, T.A. (2002). Structural basis for the transition from initia-
(2007). Selective anchoring of TFIID to nucleosomes by trimethylation of his- tion to elongation transcription in T7 RNA polymerase. Science 298, 1387–
tone H3 lysine 4. Cell 131, 58–69. 1395.
Wang, A.H., Quigley, G.J., Kolpak, F.J., Crawford, J.L., van Boom, J.H., van Zhang, G., Campbell, E.A., Minakhin, L., Richter, C., Severinov, K., and Darst,
der Marel, G., and Rich, A. (1979). Molecular structure of a left-handed double S.A. (1999). Crystal structure of Thermus aquaticus core RNA polymerase at
helical DNA fragment at atomic resolution. Nature 282, 680–686. 3.3 A resolution. Cell 98, 811–824.
Wang, D., Bushnell, D.A., Westover, K.D., Kaplan, C.D., and Kornberg, R.D. Zhang, X., Tamaru, H., Khan, S.I., Horton, J.R., Keefe, L.J., Selker, E.U., and
(2006). Structural basis of transcription: role of the trigger loop in substrate Cheng, X. (2002). Structure of the Neurospora SET domain protein DIM-5, a
specificity and catalysis. Cell 127, 941–954. histone H3 lysine methyltransferase. Cell 111, 117–127.
Wang, X., Sun, Q., Ding, Z., Ji, J., Wang, J., Kong, X., Yang, J., and Cai, G. Zhang, Y., Feng, Y., Chatterjee, S., Tuske, S., Ho, M.X., Arnold, E., and Ebright,
(2014). Redefining the modular organization of the core Mediator complex. R.H. (2012). Structural basis of transcription initiation. Science 338, 1076–
Cell Res. 24, 796–808. 1080.

994 Cell 159, November 20, 2014 ª2014 Elsevier Inc.