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PDBsum entry 2q8c
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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
2q8c

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
345 a.a. *
Ligands
ALA-ARG-M3L-SER
THR-ALA-ARG-M3L-
SER-THR-GLY-GLY
AKG ×2
Metals
_NI ×2
_ZN ×2
Waters ×199
* Residue conservation analysis
PDB id:
2q8c
Name: Oxidoreductase
Title: Crystal structure of jmjd2a in ternary complex with an histone h3k9me3 peptide and 2-oxoglutarate
Structure: Jmjc domain-containing histone demethylation protein 3a. Chain: a, b. Fragment: jumonji domain. Synonym: jumonji domain-containing protein 2a. Engineered: yes. Histone 3 peptide. Chain: f, g. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: jmjd2a, jhdm3a, jmjd2, kiaa0677. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic peptide
Resolution:
2.05Å     R-factor:   0.203     R-free:   0.236
Authors: J.-F.Couture,E.Collazo,P.Ortiz-Tello,J.S.Brunzelle,R.C.Trievel
Key ref:
J.F.Couture et al. (2007). Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nat Struct Biol, 14, 689-695. PubMed id: 17589523 DOI: 10.1038/nsmb1273
Date:
10-Jun-07     Release date:   03-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O75164  (KDM4A_HUMAN) -  Lysine-specific demethylase 4A from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1064 a.a.
345 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.1.14.11.66  - [histone H3]-trimethyl-L-lysine(9) demethylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: N6,N6,N6-trimethyl-L-lysyl9-[histone H3] + 2 2-oxoglutarate + 2 O2 = N6-methyl-L-lysyl9-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2
N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3]
Bound ligand (Het Group name = AKG)
corresponds exactly 		+ 2 × 2-oxoglutarate
 + 2 × O2
 = N(6)-methyl-L-lysyl(9)-[histone H3]
Bound ligand (Het Group name = THR)
matches with 40.00% similarity 		+
2 × formaldehyde
Bound ligand (Het Group name = ALA)
matches with 40.00% similarity 		+ 2 × succinate
 + 2 × CO2
   Enzyme class 3: E.C.1.14.11.69  - [histone H3]-trimethyl-L-lysine(36) demethylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: N6,N6,N6-trimethyl-L-lysyl36-[histone H3] + 2 2-oxoglutarate + 2 O2 = N6-methyl-L-lysyl36-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2
N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3]
Bound ligand (Het Group name = AKG)
corresponds exactly 		+ 2 × 2-oxoglutarate
 + 2 × O2
 = N(6)-methyl-L-lysyl(36)-[histone H3]
Bound ligand (Het Group name = THR)
matches with 40.00% similarity 		+
2 × formaldehyde
Bound ligand (Het Group name = ALA)
matches with 40.00% similarity 		+ 2 × succinate
 + 2 × CO2
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1038/nsmb1273 Nat Struct Biol 14:689-695 (2007)
PubMed id: 17589523  
 
 
Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase.
J.F.Couture, E.Collazo, P.A.Ortiz-Tello, J.S.Brunzelle, R.C.Trievel.
 
  ABSTRACT  
 
JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH...O) hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.
 
  Selected figure(s)  
 
Figure 1.
(a) Ribbon diagram of the JMJD2A–NOG–H3K36me3 complex, with the JmjN domain (yellow), -hairpin and mixed region (red), JmjC domain (blue) and C-terminal domain (green) depicted. NOG and H3K36me3 peptide are rendered as sticks with green and cyan carbon atoms, respectively; Ni(II) and Zn(II) atoms are in orange and gray, respectively. (b) Electrostatic surface of JMJD2A bound to KG (green carbons) and the H3K9me3 peptide (yellow carbons). Electrostatic potential is contoured from +10 k[b]T e^-1 (blue) to -10 k[b]T e^-1 (red). (c,d) Stereo views of simulated annealing F[o] - F[c] omit maps of the bound H3K36me3 (c) and H3K9me3 (d) peptides. Electron density is contoured at 2.0 . JMJD2A carbon atoms are in gray; hydrogen bonds are shown as orange dashed lines. (e,f) Schematics of the interactions between JMJD2A and the H3K36me3 (e) and H3K9me3 (f) substrates. Residues engaging in van der Waals interactions (open ellipses) and hydrogen-bonding (filled ellipses) with the histone H3 peptides are colored as in a. 		Figure 3.
(a) Active site of JMJD2A bound to KG (green carbons) and H3K9me3 (yellow carbons). Orange and green dashed lines represent conventional and CH O hydrogen bonds; blue dashed lines represent bonds coordinating Ni(II). Side chain or main chain atoms of certain residues are omitted for clarity. (b) Trimethyl -ammonium cation of H3K9me3 and methylammonium-binding pocket residue interactions. CH O hydrogen bonds are shown in green and labeled with distances. Inset, electron density of the simulated annealing omit map (contoured at 2.0 ) corresponding to the trimethylated -ammonium cation. (c,d) JMJD2A active site in complex with H3K36me3 (cyan carbons) and NOG (c) and with H3K36me2 (orange carbons) and succinate (d). Hydrogen bonds are depicted as in a.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2007, 14, 689-695) copyright 2007.  
  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.  
  21412984 K.H.Chang, O.N.King, A.Tumber, E.C.Woon, T.D.Heightman, M.A.McDonough, C.J.Schofield, and N.R.Rose (2011).
Inhibition of histone demethylases by 4-carboxy-2,2'-bipyridyl compounds.
  ChemMedChem, 6, 759-764.
PDB code: 3pdq
21460794 R.Chowdhury, K.K.Yeoh, Y.M.Tian, L.Hillringhaus, E.A.Bagg, N.R.Rose, I.K.Leung, X.S.Li, E.C.Woon, M.Yang, M.A.McDonough, O.N.King, I.J.Clifton, R.J.Klose, T.D.Claridge, P.J.Ratcliffe, C.J.Schofield, and A.Kawamura (2011).
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
  EMBO Rep, 12, 463-469.
PDB codes: 2ybk 2ybp 2ybs 2yc0 2yde
21243713 S.Krishnan, S.Horowitz, and R.C.Trievel (2011).
Structure and function of histone H3 lysine 9 methyltransferases and demethylases.
  Chembiochem, 12, 254-263.  
21220120 V.Avdic, P.Zhang, S.Lanouette, A.Groulx, V.Tremblay, J.Brunzelle, and J.F.Couture (2011).
Structural and biochemical insights into MLL1 core complex assembly.
  Structure, 19, 101-108.
PDB code: 3p4f
20084082 C.Huang, Y.Xiang, Y.Wang, X.Li, L.Xu, Z.Zhu, T.Zhang, Q.Zhu, K.Zhang, N.Jing, and C.D.Chen (2010).
Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4.
  Cell Res, 20, 154-165.  
20023638 J.R.Horton, A.K.Upadhyay, H.H.Qi, X.Zhang, Y.Shi, and X.Cheng (2010).
Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases.
  Nat Struct Mol Biol, 17, 38-43.
PDB codes: 3kv4 3kv5 3kv6 3kv9 3kva 3kvb
20101266 L.Yu, Y.Wang, S.Huang, J.Wang, Z.Deng, Q.Zhang, W.Wu, X.Zhang, Z.Liu, W.Gong, and Z.Chen (2010).
Structural insights into a novel histone demethylase PHF8.
  Cell Res, 20, 166-173.
PDB codes: 3k3n 3k3o
20210752 M.L.Bellows, and C.A.Floudas (2010).
Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.
  Curr Drug Targets, 11, 264-278.  
20373914 N.Mosammaparast, and Y.Shi (2010).
Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases.
  Annu Rev Biochem, 79, 155-179.  
21124847 O.N.King, X.S.Li, M.Sakurai, A.Kawamura, N.R.Rose, S.S.Ng, A.M.Quinn, G.Rai, B.T.Mott, P.Beswick, R.J.Klose, U.Oppermann, A.Jadhav, T.D.Heightman, D.J.Maloney, C.J.Schofield, and A.Simeonov (2010).
Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors.
  PLoS One, 5, e15535.
PDB code: 3njy
20210320 X.Cheng, and R.M.Blumenthal (2010).
Coordinated chromatin control: structural and functional linkage of DNA and histone methylation.
  Biochemistry, 49, 2999-3008.  
20679243 X.Hong, J.Zang, J.White, C.Wang, C.H.Pan, R.Zhao, R.C.Murphy, S.Dai, P.Henson, J.W.Kappler, J.Hagman, and G.Zhang (2010).
Interaction of JMJD6 with single-stranded RNA.
  Proc Natl Acad Sci U S A, 107, 14568-14572.
PDB codes: 3ld8 3ldb
21203923 X.Luo (2010).
Snapshots of a hybrid transcription factor in the Hippo pathway.
  Protein Cell, 1, 811-819.  
21067515 Y.Chang, J.Wu, X.J.Tong, J.Q.Zhou, and J.Ding (2010).
Crystal structure of the catalytic core of Saccharomyces cerevesiae histone demethylase Rph1: insights into the substrate specificity and catalytic mechanism.
  Biochem J, 433, 295-302.
PDB codes: 3opt 3opw
20567261 Y.Yang, L.Hu, P.Wang, H.Hou, Y.Lin, Y.Liu, Z.Li, R.Gong, X.Feng, L.Zhou, W.Zhang, Y.Dong, H.Yang, H.Lin, Y.Wang, C.D.Chen, and Y.Xu (2010).
Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans.
  Cell Res, 20, 886-898.
PDB codes: 3n9l 3n9m 3n9n 3n9o 3n9p 3n9q
19202064 A.Tzatsos, R.Pfau, S.C.Kampranis, and P.N.Tsichlis (2009).
Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus.
  Proc Natl Acad Sci U S A, 106, 2641-2646.  
18603028 B.C.Smith, and J.M.Denu (2009).
Chemical mechanisms of histone lysine and arginine modifications.
  Biochim Biophys Acta, 1789, 45-57.  
19464317 B.Illi, C.Colussi, A.Grasselli, A.Farsetti, M.C.Capogrossi, and C.Gaetano (2009).
NO sparks off chromatin: tales of a multifaceted epigenetic regulator.
  Pharmacol Ther, 123, 344-352.  
19845621 J.Yang, I.Ledaki, H.Turley, K.C.Gatter, J.C.Montero, J.L.Li, and A.L.Harris (2009).
Role of hypoxia-inducible factors in epigenetic regulation via histone demethylases.
  Ann N Y Acad Sci, 1177, 185-197.  
18923809 S.S.Ng, W.W.Yue, U.Oppermann, and R.J.Klose (2009).
Dynamic protein methylation in chromatin biology.
  Cell Mol Life Sci, 66, 407-422.  
19088188 J.F.Couture, L.M.Dirk, J.S.Brunzelle, R.L.Houtz, and R.C.Trievel (2008).
Structural origins for the product specificity of SET domain protein methyltransferases.
  Proc Natl Acad Sci U S A, 105, 20659-20664.
PDB codes: 3f9w 3f9x 3f9y 3f9z
18084306 J.Lee, J.R.Thompson, M.V.Botuyan, and G.Mer (2008).
Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor.
  Nat Struct Mol Biol, 15, 109-111.
PDB codes: 2qqr 2qqs
18813363 J.M.Simmons, T.A.Müller, and R.P.Hausinger (2008).
Fe(II)/alpha-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism.
  Dalton Trans, (), 5132-5142.  
18375980 M.Lloret-Llinares, C.Carré, A.Vaquero, N.de Olano, and F.Azorín (2008).
Characterization of Drosophila melanogaster JmjC+N histone demethylases.
  Nucleic Acids Res, 36, 2852-2863.  
18451103 P.A.Cloos, J.Christensen, K.Agger, and K.Helin (2008).
Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease.
  Genes Dev, 22, 1115-1140.  
17988933 G.Kustatscher, and A.G.Ladurner (2007).
Modular paths to 'decoding' and 'wiping' histone lysine methylation.
  Curr Opin Chem Biol, 11, 628-635.  
17851108 J.C.Culhane, and P.A.Cole (2007).
LSD1 and the chemistry of histone demethylation.
  Curr Opin Chem Biol, 11, 561-568.  
17676028 J.R.Wilson (2007).
Targeting the JMJD2A histone lysine demethylase.
  Nat Struct Mol Biol, 14, 682-684.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
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.

 

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