4U7T

Crystal structure of DNMT3A-DNMT3L in complex with histone H3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 

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This is version 1.3 of the entry. See complete history


Literature

Structural insight into autoinhibition and histone H3-induced activation of DNMT3A

Guo, X.Wang, L.Li, J.Ding, Z.Xiao, J.Yin, X.He, S.Shi, P.Dong, L.Li, G.Tian, C.Wang, J.Cong, Y.Xu, Y.

(2015) Nature 517: 640-644

  • DOI: https://doi.org/10.1038/nature13899
  • Primary Citation of Related Structures:  
    4U7P, 4U7T

  • PubMed Abstract: 

    DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.


  • Organizational Affiliation

    1] Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [2] State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA (cytosine-5)-methyltransferase 3A
A, C
445Homo sapiensMutation(s): 0 
Gene Names: DNMT3A
EC: 2.1.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6K1 (Homo sapiens)
Explore Q9Y6K1 
Go to UniProtKB:  Q9Y6K1
PHAROS:  Q9Y6K1
GTEx:  ENSG00000119772 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6K1
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
DNA (cytosine-5)-methyltransferase 3-like
B, D
209Homo sapiensMutation(s): 0 
Gene Names: DNMT3L
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UJW3 (Homo sapiens)
Explore Q9UJW3 
Go to UniProtKB:  Q9UJW3
PHAROS:  Q9UJW3
GTEx:  ENSG00000142182 
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UniProt GroupQ9UJW3
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
peptide from Histone H3.3E [auth F],
F [auth G]
12Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P84243 (Homo sapiens)
Explore P84243 
Go to UniProtKB:  P84243
PHAROS:  P84243
Entity Groups  
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UniProt GroupP84243
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 183.823α = 90
b = 183.823β = 90
c = 123.265γ = 120
Software Package:
Software NamePurpose
HKL-2000data reduction
PHASERphasing
PDB_EXTRACTdata extraction
Cootmodel building
PHENIXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-11-12
    Type: Initial release
  • Version 1.1: 2014-12-17
    Changes: Database references
  • Version 1.2: 2015-02-04
    Changes: Database references
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy