2OQ6

Crystal structure of JMJD2A complexed with histone H3 peptide trimethylated at Lys9


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.

Ng, S.S.Kavanagh, K.L.McDonough, M.A.Butler, D.Pilka, E.S.Lienard, B.M.Bray, J.E.Savitsky, P.Gileadi, O.von Delft, F.Rose, N.R.Offer, J.Scheinost, J.C.Borowski, T.Sundstrom, M.Schofield, C.J.Oppermann, U.

(2007) Nature 448: 87-91

  • DOI: https://doi.org/10.1038/nature05971
  • Primary Citation of Related Structures:  
    2OQ6, 2OQ7, 2OS2, 2OT7, 2OX0

  • PubMed Abstract: 

    Post-translational histone modification has a fundamental role in chromatin biology and is proposed to constitute a 'histone code' in epigenetic regulation. Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochromatin formation, X-chromosome inactivation, genome imprinting, DNA repair and transcriptional regulation. The discovery of lysyl demethylases using flavin (amine oxidases) or Fe(II) and 2-oxoglutarate as cofactors (2OG oxygenases) has changed the view of methylation as a stable epigenetic marker. However, little is known about how the demethylases are selective for particular lysyl-containing sequences in specific methylation states, a key to understanding their functions. Here we reveal how human JMJD2A (jumonji domain containing 2A), which is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9. We report structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. We propose a mechanism for achieving methylation state selectivity involving the orientation of the substrate methyl groups towards a ferryl intermediate. The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.


  • Organizational Affiliation

    Structural Genomics Consortium, Botnar Research Center, University of Oxford, Oxford OX3 7LD, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
JmjC domain-containing histone demethylation protein 3A
A, B
381Homo sapiensMutation(s): 0 
Gene Names: JMJD2AJHDM3AJMJD2KIAA0677
EC: 1.14.11
UniProt & NIH Common Fund Data Resources
Find proteins for O75164 (Homo sapiens)
Explore O75164 
Go to UniProtKB:  O75164
PHAROS:  O75164
GTEx:  ENSG00000066135 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75164
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
synthetic peptide
C, D
8N/AMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P68431 (Homo sapiens)
Explore P68431 
Go to UniProtKB:  P68431
PHAROS:  P68431
Entity Groups  
UniProt GroupP68431
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
ALY
Query on ALY
C, D
L-PEPTIDE LINKINGC8 H16 N2 O3LYS
M3L
Query on M3L
C, D
L-PEPTIDE LINKINGC9 H21 N2 O2LYS
Binding Affinity Annotations 
IDSourceBinding Affinity
OGA PDBBind:  2OQ6 IC50: 2.50e+5 (nM) from 1 assay(s)
BindingDB:  2OQ6 IC50: min: 8.50e+4, max: 2.50e+5 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.165 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.347α = 90
b = 149.88β = 90
c = 57.26γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
CCP4data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-03-13
    Type: Initial release
  • Version 1.1: 2007-10-15
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Refinement description, Version format compliance
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Derived calculations