PDBsum entry 1h3i

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Transferase PDB id
Protein chain
293 a.a. *
_MG ×3
Waters ×344
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of the histone methyltransferase set7/9
Structure: Histone h3 lysine 4 specific methyltransferase. Chain: a, b. Fragment: n-domain, set-domain, residues 52-344. Synonym: histone h3-k4, methyltransferase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Monomer (from PDB file)
2.10Å     R-factor:   0.212     R-free:   0.255
Authors: J.R.Wilson,C.Jing,P.A.Walker,S.R.Martin,S.A.Howell, G.M.Blackburn,S.J.Gamblin,B.Xiao
Key ref:
J.R.Wilson et al. (2002). Crystal structure and functional analysis of the histone methyltransferase SET7/9. Cell, 111, 105-115. PubMed id: 12372304 DOI: 10.1016/S0092-8674(02)00964-9
04-Sep-02     Release date:   11-Nov-02    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q8WTS6  (SETD7_HUMAN) -  Histone-lysine N-methyltransferase SETD7
366 a.a.
293 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - 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]
+ 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!
  Cellular component     chromosome   1 term 
  Biological process     regulation of transcription, DNA-dependent   2 terms 
  Biochemical function     histone-lysine N-methyltransferase activity     1 term  


    Added reference    
DOI no: 10.1016/S0092-8674(02)00964-9 Cell 111:105-115 (2002)
PubMed id: 12372304  
Crystal structure and functional analysis of the histone methyltransferase SET7/9.
J.R.Wilson, C.Jing, P.A.Walker, S.R.Martin, S.A.Howell, G.M.Blackburn, S.J.Gamblin, B.Xiao.
Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. The evolutionarily conserved SET domain occurs in most proteins known to possess histone lysine methyltransferase activity. We present here the crystal structure of a large fragment of human SET7/9 that contains a N-terminal beta-sheet domain as well as the conserved SET domain. Mutagenesis identifies two residues in the C terminus of the protein that appear essential for catalytic activity toward lysine-4 of histone H3. Furthermore, we show how the cofactor AdoMet binds to this domain and present biochemical data supporting the role of invariant residues in catalysis, binding of AdoMet, and interactions with the peptide substrate.
  Selected figure(s)  
Figure 1.
Figure 1. The Structure of SET7/9(A) Two orthogonal views of the structure are shown in ribbon representation. The N domain (residues 52–192) is colored green, the loop connecting the N domain with the conserved core of the SET domain is colored blue, and the SET domain is colored yellow. The secondary structure elements are labeled.(B) A stereographic representation of the Cα trace of the SET domain colored and oriented as the right-hand panel of (A); every 20^th residue is labeled.(C) Schematic representation of the topology of the SET domain colored as in (A). β-strands are shown as triangles and helical segments as circles, the N terminus of the SET domain (residue 193) is indicated by an open circle, and the last residue in the crystal structure (344) by the solid arrowhead. The C terminus forms a threaded loop through the central 3[10]-β20 connection.(D) The molecular surface of the N domain of SET7/9 is colored according to its electrostatic potential as calculated using GRASP. Negative electrostatic potential is red, with positive electrostatic potential blue. The molecule is oriented as in the left panel of (A).
Figure 2.
Figure 2. Conservation of Residues across the SET Family(A) Sequence alignment of SET7/9 with a subset of other SET domains. The entire coding sequence of SET7/9 is shown together with the secondary structure elements assigned from the crystal structure, colored according to Figure 1A. The aligned sequences are from PR-Set07 (AAF97812), human G9a (S30385), human SUV39H1 (NP003164), and set2 (NP012367). The sequences were aligned using Clustalw. Residues invariant across these domains are boxed in blue, while two conservatively substituted residues are boxed in light blue. The extent of the crystal structure is indicated by the red line.(B) Surface representation of SET domain with conserved residues colored according to (A) with the three conserved regions labeled.
  The above figures are reprinted by permission from Cell Press: Cell (2002, 111, 105-115) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21190999 D.B.Yap, J.Chu, T.Berg, M.Schapira, S.W.Cheng, A.Moradian, R.D.Morin, A.J.Mungall, B.Meissner, M.Boyle, V.E.Marquez, M.A.Marra, R.D.Gascoyne, R.K.Humphries, C.H.Arrowsmith, G.B.Morin, and S.A.Aparicio (2011).
Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation.
  Blood, 117, 2451-2459.  
21119616 S.M.Carr, S.Munro, B.Kessler, U.Oppermann, and N.B.La Thangue (2011).
Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein.
  EMBO J, 30, 317-327.  
21124902 F.Cao, Y.Chen, T.Cierpicki, Y.Liu, V.Basrur, M.Lei, and Y.Dou (2010).
An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain.
  PLoS One, 5, e14102.  
20937900 H.Wei, and M.M.Zhou (2010).
Dimerization of a viral SET protein endows its function.
  Proc Natl Acad Sci U S A, 107, 18433-18438.
PDB codes: 3kma 3kmj 3kmt
20107052 K.L.Mecklenburg, N.Takemori, N.Komori, B.Chu, R.C.Hardie, H.Matsumoto, and J.E.O'Tousa (2010).
Retinophilin is a light-regulated phosphoprotein required to suppress photoreceptor dark noise in Drosophila.
  J Neurosci, 30, 1238-1249.  
20140018 S.Munro, N.Khaire, A.Inche, S.Carr, and N.B.La Thangue (2010).
Lysine methylation regulates the pRb tumour suppressor protein.
  Oncogene, 29, 2357-2367.  
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.  
19822661 J.N.Psathas, S.Zheng, S.Tan, and J.C.Reese (2009).
Set2-dependent K36 methylation is regulated by novel intratail interactions within H3.
  Mol Cell Biol, 29, 6413-6426.  
19923717 L.J.Wu, T.Zhang, Y.X.Gu, C.D.Zheng, and H.F.Fan (2009).
Direct-method SAD phasing of proteins enhanced by the use of intrinsic bimodal phase distributions in the subsequent phase-improvement process.
  Acta Crystallogr D Biol Crystallogr, 65, 1213-1216.  
19362589 M.J.Hitchler, and F.E.Domann (2009).
Metabolic defects provide a spark for the epigenetic switch in cancer.
  Free Radic Biol Med, 47, 115-127.  
  19684477 S.Pradhan, H.G.Chin, P.O.Estève, and S.E.Jacobsen (2009).
SET7/9 mediated methylation of non-histone proteins in mammalian cells.
  Epigenetics, 4, 383-387.  
19262565 X.D.Yang, B.Huang, M.Li, A.Lamb, N.L.Kelleher, and L.F.Chen (2009).
Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit.
  EMBO J, 28, 1055-1066.  
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.  
18693240 P.Joshi, E.A.Carrington, L.Wang, C.S.Ketel, E.L.Miller, R.S.Jones, and J.A.Simon (2008).
Dominant Alleles Identify SET Domain Residues Required for Histone Methyltransferase of Polycomb Repressive Complex 2.
  J Biol Chem, 283, 27757-27766.  
18650421 Y.Li, M.A.Reddy, F.Miao, N.Shanmugam, J.K.Yee, D.Hawkins, B.Ren, and R.Natarajan (2008).
Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation.
  J Biol Chem, 283, 26771-26781.  
17517655 H.B.Guo, and H.Guo (2007).
Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity.
  Proc Natl Acad Sci U S A, 104, 8797-8802.  
17470555 J.Fang, G.J.Hogan, G.Liang, J.D.Lieb, and Y.Zhang (2007).
The Saccharomyces cerevisiae histone demethylase Jhd1 fine-tunes the distribution of H3K36me2.
  Mol Cell Biol, 27, 5055-5065.  
17761298 M.J.Hitchler, and F.E.Domann (2007).
An epigenetic perspective on the free radical theory of development.
  Free Radic Biol Med, 43, 1023-1036.  
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.  
17327221 T.R.Porras-Yakushi, J.P.Whitelegge, and S.Clarke (2007).
Yeast ribosomal/cytochrome c SET domain methyltransferase subfamily: identification of Rpl23ab methylation sites and recognition motifs.
  J Biol Chem, 282, 12368-12376.  
17374386 X.Cheng, and X.Zhang (2007).
Structural dynamics of protein lysine methylation and demethylation.
  Mutat Res, 618, 102-115.  
16415881 J.F.Couture, E.Collazo, G.Hauk, and R.C.Trievel (2006).
Structural basis for the methylation site specificity of SET7/9.
  Nat Struct Mol Biol, 13, 140-146.
PDB code: 2f69
16682405 J.F.Couture, G.Hauk, M.J.Thompson, G.M.Blackburn, and R.C.Trievel (2006).
Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases.
  J Biol Chem, 281, 19280-19287.
PDB codes: 2h21 2h23 2h2e 2h2j
16622709 J.Mis, S.S.Ner, and T.A.Grigliatti (2006).
Identification of three histone methyltransferases in Drosophila: dG9a is a suppressor of PEV and is required for gene silencing.
  Mol Genet Genomics, 275, 513-526.  
16829525 M.S.Kareta, Z.M.Botello, J.J.Ennis, C.Chou, and F.Chédin (2006).
Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L.
  J Biol Chem, 281, 25893-25902.  
15933069 B.Xiao, C.Jing, G.Kelly, P.A.Walker, F.W.Muskett, T.A.Frenkiel, S.R.Martin, K.Sarma, D.Reinberg, S.J.Gamblin, and J.R.Wilson (2005).
Specificity and mechanism of the histone methyltransferase Pr-Set7.
  Genes Dev, 19, 1444-1454.
PDB code: 2bqz
15935324 H.Gowher, X.Zhang, X.Cheng, and A.Jeltsch (2005).
Avidin plate assay system for enzymatic characterization of a histone lysine methyltransferase.
  Anal Biochem, 342, 287-291.  
15933070 J.F.Couture, E.Collazo, J.S.Brunzelle, and R.C.Trievel (2005).
Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase.
  Genes Dev, 19, 1455-1465.
PDB code: 1zkk
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.  
16086857 S.C.Dillon, X.Zhang, R.C.Trievel, and X.Cheng (2005).
The SET-domain protein superfamily: protein lysine methyltransferases.
  Genome Biol, 6, 227.  
15869391 X.Cheng, R.E.Collins, and X.Zhang (2005).
Structural and sequence motifs of protein (histone) methylation enzymes.
  Annu Rev Biophys Biomol Struct, 34, 267-294.  
15964846 Y.Yin, C.Liu, S.N.Tsai, B.Zhou, S.M.Ngai, and G.Zhu (2005).
SET8 recognizes the sequence RHRK20VLRDN within the N terminus of histone H4 and mono-methylates lysine 20.
  J Biol Chem, 280, 30025-30031.  
15213386 J.W.Wang, J.R.Chen, Y.X.Gu, C.D.Zheng, F.Jiang, H.F.Fan, T.C.Terwilliger, and Q.Hao (2004).
SAD phasing by combination of direct methods with the SOLVE/RESOLVE procedure.
  Acta Crystallogr D Biol Crystallogr, 60, 1244-1253.  
15502306 J.W.Wang, J.R.Chen, Y.X.Gu, C.D.Zheng, F.Jiang, and H.F.Fan (2004).
Optimizing the error term in direct-method SAD phasing.
  Acta Crystallogr D Biol Crystallogr, 60, 1987-1990.  
12540855 B.Xiao, C.Jing, J.R.Wilson, P.A.Walker, N.Vasisht, G.Kelly, S.Howell, I.A.Taylor, G.M.Blackburn, and S.J.Gamblin (2003).
Structure and catalytic mechanism of the human histone methyltransferase SET7/9.
  Nature, 421, 652-656.
PDB code: 1o9s
14675547 B.Xiao, J.R.Wilson, and S.J.Gamblin (2003).
SET domains and histone methylation.
  Curr Opin Struct Biol, 13, 699-705.  
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.  
12917322 J.Landry, A.Sutton, T.Hesman, J.Min, R.M.Xu, M.Johnston, and R.Sternglanz (2003).
Set2-catalyzed methylation of histone H3 represses basal expression of GAL4 in Saccharomyces cerevisiae.
  Mol Cell Biol, 23, 5972-5978.  
12628190 J.Min, Q.Feng, Z.Li, Y.Zhang, and R.M.Xu (2003).
Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase.
  Cell, 112, 711-723.
PDB code: 1nw3
12567185 K.L.Manzur, A.Farooq, L.Zeng, O.Plotnikova, A.W.Koch, Sachchidanand, and M.M.Zhou (2003).
A dimeric viral SET domain methyltransferase specific to Lys27 of histone H3.
  Nat Struct Biol, 10, 187-196.
PDB code: 1n3j
12819771 R.C.Trievel, E.M.Flynn, R.L.Houtz, and J.H.Hurley (2003).
Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT.
  Nat Struct Biol, 10, 545-552.
PDB codes: 1ozv 1p0y
12575990 R.Marmorstein (2003).
Structure of SET domain proteins: a new twist on histone methylation.
  Trends Biochem Sci, 28, 59-62.  
12514135 T.Kwon, J.H.Chang, E.Kwak, C.W.Lee, A.Joachimiak, Y.C.Kim, J.Lee, and Y.Cho (2003).
Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet.
  EMBO J, 22, 292-303.
PDB codes: 1n6a 1n6c
12887903 X.Zhang, Z.Yang, S.I.Khan, J.R.Horton, H.Tamaru, E.U.Selker, and X.Cheng (2003).
Structural basis for the product specificity of histone lysine methyltransferases.
  Mol Cell, 12, 177-185.
PDB code: 1peg
12447351 R.N.Dutnall, and J.M.Denu (2002).
Methyl magic and HAT tricks.
  Nat Struct Biol, 9, 888-891.  
12372294 T.O.Yeates (2002).
Structures of SET domain proteins: protein lysine methyltransferases make their mark.
  Cell, 111, 5-7.  
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 codes are shown on the right.