4YOC

Crystal Structure of human DNMT1 and USP7/HAUSP complex

Summary for 4YOC

• Entry DOI: 10.2210/pdb4yoc/pdb
• Descriptor: DNA (cytosine-5)-methyltransferase 1, Ubiquitin carboxyl-terminal hydrolase 7, ZINC ION, ... (4 entities in total)
• Functional Keywords: dna methylation, deubiquitination, dna methyltransferase, modification, transferase-hydrolase complex, transferase/hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P26358 Q93009
• Total number of polymer chains: 2
• Total formula weight: 178153.66

Authors

Cheng, J.,Yang, H.,Fang, J.,Gong, R.,Wang, P.,Li, Z.,Xu, Y. (deposition date: 2015-03-11, release date: 2015-05-27, Last modification date: 2023-11-08)

Primary citation

Cheng, J.,Yang, H.,Fang, J.,Ma, L.,Gong, R.,Wang, P.,Li, Z.,Xu, Y.
Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.
Nat Commun, 6:7023-7023, 2015

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.

PubMed: 25960197
DOI: 10.1038/ncomms8023

Experimental method

X-RAY DIFFRACTION (2.916 Å)