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PDBsum entry 1nw3

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protein ligands links
Transferase PDB id
1nw3
Jmol
Contents
Protein chain
328 a.a. *
Ligands
ACT
SO4 ×2
SAM
Waters ×68
* Residue conservation analysis
PDB id:
1nw3
Name: Transferase
Title: Structure of the catalytic domain of human dot1l, a non-set nucleosomal histone methyltransferase
Structure: Histone methyltransferase dot1l. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: dot1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.50Å     R-factor:   0.204     R-free:   0.246
Authors: J.R.Min,Q.Feng,Z.H.Li,Y.Zhang,R.M.Xu
Key ref:
J.Min et al. (2003). Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell, 112, 711-723. PubMed id: 12628190 DOI: 10.1016/S0092-8674(03)00114-4
Date:
05-Feb-03     Release date:   25-Mar-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8TEK3  (DOT1L_HUMAN) -  Histone-lysine N-methyltransferase, H3 lysine-79 specific
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1739 a.a.
328 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.1.1.43  - Histone-lysine N-methyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N6-methyl-L-lysine-[histone]
S-adenosyl-L-methionine
Bound ligand (Het Group name = SAM)
corresponds exactly
+ L-lysine-[histone]
= S-adenosyl-L-homocysteine
+ N(6)-methyl-L-lysine-[histone]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     histone-lysine N-methyltransferase activity     1 term  

 

 
    Added reference    
 
 
DOI no: 10.1016/S0092-8674(03)00114-4 Cell 112:711-723 (2003)
PubMed id: 12628190  
 
 
Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase.
J.Min, Q.Feng, Z.Li, Y.Zhang, R.M.Xu.
 
  ABSTRACT  
 
Dot1 is an evolutionarily conserved histone methyltransferase that methylates lysine-79 of histone H3 in the core domain. Unlike other histone methyltransferases, Dot1 does not contain a SET domain, and it specifically methylates nucleosomal histone H3. We have solved a 2.5 A resolution structure of the catalytic domain of human Dot1, hDOT1L, in complex with S-adenosyl-L-methionine (SAM). The structure reveals a unique organization of a mainly alpha-helical N-terminal domain and a central open alpha/beta structure, an active site consisting of a SAM binding pocket, and a potential lysine binding channel. We also show that a flexible, positively charged region at the C terminus of the catalytic domain is critical for nucleosome binding and enzymatic activity. These structural and biochemical analyses, combined with molecular modeling, provide mechanistic insights into the catalytic mechanism and nucleosomal specificity of Dot1 proteins.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. The Overall Structure of hDOT1L(1–416)(A) Ribbon diagram of the hDOT1L(1–416) structure. The N-terminal region (aa 1–126) is colored yellow, the open α/β structure (aa 141–332) is shown in cyan, and the loop L-EF connecting the two regions is shown in red. The bound SAM molecule is shown in a ball-and-stick model (carbon, gray; nitrogen, blue; oxygen, red; sulfur, yellow).(B) Topological diagram of hDOT1L(1–416). Secondary structure elements are colored using the same scheme as in (A). Helices are labeled alphabetically and strands are numbered numerically in an order from the N- to the C terminus. The position of the SAM binding site is also indicated.
Figure 6.
Figure 6. Structure Comparison and Modeling of hDOT1L-Nucleosome Core Particle Interaction(A) The structure of catechol O-methyltransferase is shown in a ribbon diagram. The open α/β structure is colored cyan, the inter-domain linker is colored red, and other regions are colored yellow. SAM and a catechol-like inhibitor are shown as stick-and-ball models. The inhibitor is colored magenta, and the coloring scheme for SAM is: carbon, green; nitrogen, blue; oxygen, red; sulfur, magenta.(B) The structure of P. furiosus L-isoaspartyl methyltransferase complexed with adenosine and a methyl accepting peptide. The same coloring scheme for the protein and adenosine (as for SAM), as in (A), is used. The peptide main chain and the side chain of the methyl acceptor L-isoaspartate (ball-and-stick) are shown in magenta.(C) The structure of hDOT1L(1–416) in a ribbon representation, colored as in (A). All three structures shown in (A)–(C) are orientated similarly.(D) The modeled hDOT1L(1–416)-nucleosome core particle complex viewed along the superhelical axis. DNA is shown in a ribbon representation (gray) and hDOT1L(1–416) is colored as in (C), except that yellow is changed to orange. SAM is shown as a green CPK model. Histones are shown in surface models (H3, blue; H4, gold; H2A, light gray; H2B, dark gray).(E) A side view of the same model, as shown in (D).
 
  The above figures are reprinted by permission from Cell Press: Cell (2003, 112, 711-723) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21141727 A.K.Upadhyay, and X.Cheng (2011).
Dynamics of histone lysine methylation: structures of methyl writers and erasers.
  Prog Drug Res, 67, 107-124.  
21243718 F.Frederiks, I.J.Stulemeijer, H.Ovaa, and F.van Leeuwen (2011).
A modified epigenetics toolbox to study histone modifications on the nucleosome core.
  Chembiochem, 12, 308-313.  
21291527 I.J.Stulemeijer, B.L.Pike, A.W.Faber, K.F.Verzijlbergen, T.van Welsem, F.Frederiks, T.L.Lenstra, F.C.Holstege, S.M.Gasser, and F.van Leeuwen (2011).
Dot1 binding induces chromatin rearrangements by histone methylation-dependent and -independent mechanisms.
  Epigenetics Chromatin, 4, 2.  
21398221 S.Y.Jo, E.M.Granowicz, I.Maillard, D.Thomas, and J.L.Hess (2011).
Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation.
  Blood, 117, 4759-4768.  
20203130 M.Mohan, H.M.Herz, Y.H.Takahashi, C.Lin, K.C.Lai, Y.Zhang, M.P.Washburn, L.Florens, and A.Shilatifard (2010).
Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom).
  Genes Dev, 24, 574-589.  
19489729 A.Edwards (2009).
Large-scale structural biology of the human proteome.
  Annu Rev Biochem, 78, 541-568.  
19556245 A.Patel, V.Dharmarajan, V.E.Vought, and M.S.Cosgrove (2009).
On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex.
  J Biol Chem, 284, 24242-24256.  
18603028 B.C.Smith, and J.M.Denu (2009).
Chemical mechanisms of histone lysine and arginine modifications.
  Biochim Biophys Acta, 1789, 45-57.  
18818687 D.Zhang, Z.Y.Yu, P.Cruz, Q.Kong, S.Li, and B.C.Kone (2009).
Epigenetics and the control of epithelial sodium channel expression in collecting duct.
  Kidney Int, 75, 260-267.  
19734945 F.V.Jacinto, E.Ballestar, and M.Esteller (2009).
Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation.
  Oncogene, 28, 4212-4224.  
19289854 M.Liedtke, and M.L.Cleary (2009).
Therapeutic targeting of MLL.
  Blood, 113, 6061-6068.  
19721445 R.A.Copeland, M.E.Solomon, and V.M.Richon (2009).
Protein methyltransferases as a target class for drug discovery.
  Nat Rev Drug Discov, 8, 724-732.  
18485871 A.Murayama, K.Ohmori, A.Fujimura, H.Minami, K.Yasuzawa-Tanaka, T.Kuroda, S.Oie, H.Daitoku, M.Okuwaki, K.Nagata, A.Fukamizu, K.Kimura, T.Shimizu, and J.Yanagisawa (2008).
Epigenetic control of rDNA loci in response to intracellular energy status.
  Cell, 133, 627-639.
PDB code: 2zfu
18285465 D.J.Steger, M.I.Lefterova, L.Ying, A.J.Stonestrom, M.Schupp, D.Zhuo, A.L.Vakoc, J.E.Kim, J.Chen, M.A.Lazar, G.A.Blobel, and C.R.Vakoc (2008).
DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.
  Mol Cell Biol, 28, 2825-2839.  
18511943 F.Frederiks, M.Tzouros, G.Oudgenoeg, T.van Welsem, M.Fornerod, J.Krijgsveld, and F.van Leeuwen (2008).
Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states.
  Nat Struct Mol Biol, 15, 550-557.  
18980680 H.Watanabe, K.Soejima, H.Yasuda, I.Kawada, I.Nakachi, S.Yoda, K.Naoki, and A.Ishizaka (2008).
Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells.
  Cancer Cell Int, 8, 15.  
18710950 K.R.Badri, Y.Zhou, U.Dhru, S.Aramgam, and L.Schuger (2008).
Effects of the SANT domain of tension-induced/inhibited proteins (TIPs), novel partners of the histone acetyltransferase p300, on p300 activity and TIP-6-induced adipogenesis.
  Mol Cell Biol, 28, 6358-6372.  
18311969 P.Hu, S.Wang, and Y.Zhang (2008).
How do SET-domain protein lysine methyltransferases achieve the methylation state specificity? Revisited by Ab initio QM/MM molecular dynamics simulations.
  J Am Chem Soc, 130, 3806-3813.  
18449190 R.K.McGinty, J.Kim, C.Chatterjee, R.G.Roeder, and T.W.Muir (2008).
Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation.
  Nature, 453, 812-816.  
18441235 T.Sawado, J.Halow, H.Im, T.Ragoczy, E.H.Bresnick, M.A.Bender, and M.Groudine (2008).
H3 K79 dimethylation marks developmental activation of the beta-globin gene but is reduced upon LCR-mediated high-level transcription.
  Blood, 112, 406-414.  
18391193 X.Zhang, and T.C.Bruice (2008).
Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases.
  Proc Natl Acad Sci U S A, 105, 5728-5732.  
17675446 I.M.Fingerman, H.C.Li, and S.D.Briggs (2007).
A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing: identification of a new trans-histone pathway.
  Genes Dev, 21, 2018-2029.  
18158898 M.Altaf, R.T.Utley, N.Lacoste, S.Tan, S.D.Briggs, and J.Côté (2007).
Interplay of chromatin modifiers on a short basic patch of histone H4 tail defines the boundary of telomeric heterochromatin.
  Mol Cell, 28, 1002-1014.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
17388541 S.Wang, P.Hu, and Y.Zhang (2007).
Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: the case of histone lysine methyltransferase SET7/9.
  J Phys Chem B, 111, 3758-3764.  
17332896 W.Zhang, X.Xia, M.R.Reisenauer, T.Rieg, F.Lang, D.Kuhl, V.Vallon, and B.C.Kone (2007).
Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha.
  J Clin Invest, 117, 773-783.  
17374386 X.Cheng, and X.Zhang (2007).
Structural dynamics of protein lysine methylation and demethylation.
  Mutat Res, 618, 102-115.  
16714444 E.L.Mersfelder, and M.R.Parthun (2006).
The tale beyond the tail: histone core domain modifications and the regulation of chromatin structure.
  Nucleic Acids Res, 34, 2653-2662.  
17070031 J.F.Couture, and R.C.Trievel (2006).
Histone-modifying enzymes: encrypting an enigmatic epigenetic code.
  Curr Opin Struct Biol, 16, 753-760.  
16636056 W.Zhang, X.Xia, M.R.Reisenauer, C.S.Hemenway, and B.C.Kone (2006).
Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner.
  J Biol Chem, 281, 18059-18068.  
16094449 A.Wood, J.Schneider, and A.Shilatifard (2005).
Cross-talking histones: implications for the regulation of gene expression and DNA repair.
  Biochem Cell Biol, 83, 460-467.  
15898057 M.Biel, V.Wascholowski, and A.Giannis (2005).
Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes.
  Angew Chem Int Ed Engl, 44, 3186-3216.  
16039595 M.D.Shahbazian, K.Zhang, and M.Grunstein (2005).
Histone H2B ubiquitylation controls processive methylation but not monomethylation by Dot1 and Set1.
  Mol Cell, 19, 271-277.  
16225687 P.Z.Kozbial, and A.R.Mushegian (2005).
Natural history of S-adenosylmethionine-binding proteins.
  BMC Struct Biol, 5, 19.  
16166626 R.Wysocki, A.Javaheri, S.Allard, F.Sha, J.Côté, and S.J.Kron (2005).
Role of Dot1-dependent histone H3 methylation in G1 and S phase DNA damage checkpoint functions of Rad9.
  Mol Cell Biol, 25, 8430-8443.  
15851025 Y.Okada, Q.Feng, Y.Lin, Q.Jiang, Y.Li, V.M.Coffield, L.Su, G.Xu, and Y.Zhang (2005).
hDOT1L links histone methylation to leukemogenesis.
  Cell, 121, 167-178.  
15292170 K.Sawada, Z.Yang, J.R.Horton, R.E.Collins, X.Zhang, and X.Cheng (2004).
Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase.
  J Biol Chem, 279, 43296-43306.
PDB code: 1u2z
15146494 L.M.Iyer, and L.Aravind (2004).
The emergence of catalytic and structural diversity within the beta-clip fold.
  Proteins, 55, 977-991.  
14675547 B.Xiao, J.R.Wilson, and S.J.Gamblin (2003).
SET domains and histone methylation.
  Curr Opin Struct Biol, 13, 699-705.  
12876293 H.H.Ng, S.Dole, and K.Struhl (2003).
The Rtf1 component of the Paf1 transcriptional elongation complex is required for ubiquitination of histone H2B.
  J Biol Chem, 278, 33625-33628.  
12826405 H.L.Schubert, R.M.Blumenthal, and X.Cheng (2003).
Many paths to methyltransfer: a chronicle of convergence.
  Trends Biochem Sci, 28, 329-335.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.