4YOC

Crystal Structure of human DNMT1 and USP7/HAUSP complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.92 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.

Cheng, J.Yang, H.Fang, J.Ma, L.Gong, R.Wang, P.Li, Z.Xu, Y.

(2015) Nat Commun 6: 7023-7023

  • DOI: https://doi.org/10.1038/ncomms8023
  • Primary Citation of Related Structures:  
    4YOC

  • PubMed Abstract: 

    DNMT1 is an important epigenetic regulator that plays a key role in the maintenance of DNA methylation. Here we determined the crystal structure of DNMT1 in complex with USP7 at 2.9 Å resolution. The interaction between the two proteins is primarily mediated by an acidic pocket in USP7 and Lysine residues within DNMT1's KG linker. This intermolecular interaction is required for USP7-mediated stabilization of DNMT1. Acetylation of the KG linker Lysine residues impair DNMT1-USP7 interaction and promote the degradation of DNMT1. Treatment with HDAC inhibitors results in an increase in acetylated DNMT1 and decreased total DNMT1 protein. This negative correlation is observed in differentiated neuronal cells and pancreatic cancer cells. Our studies reveal that USP7-mediated stabilization of DNMT1 is regulated by acetylation and provide a structural basis for the design of inhibitors, targeting the DNMT1-USP7 interaction surface for therapeutic applications.


  • Organizational Affiliation

    1] Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China [2] Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [3] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA (cytosine-5)-methyltransferase 11,004Homo sapiensMutation(s): 0 
Gene Names: DNMT1AIMCXXC9DNMT
EC: 2.1.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for P26358 (Homo sapiens)
Explore P26358 
Go to UniProtKB:  P26358
PHAROS:  P26358
GTEx:  ENSG00000130816 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26358
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Ubiquitin carboxyl-terminal hydrolase 7B [auth C]548Homo sapiensMutation(s): 0 
Gene Names: USP7HAUSP
EC: 3.4.19.12
UniProt & NIH Common Fund Data Resources
Find proteins for Q93009 (Homo sapiens)
Explore Q93009 
Go to UniProtKB:  Q93009
PHAROS:  Q93009
GTEx:  ENSG00000187555 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ93009
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.92 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.231α = 90
b = 111.619β = 90
c = 163.868γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data collection
HKL-2000data scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-05-27
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy