7XIB

Cryo-EM structure of human DNMT1 (aa:351-1616) in complex with ubiquitinated H3 and hemimethylated DNA analog (CXXC-disordered form)

This is a non-PDB format compatible entry.

Summary for 7XIB

• Entry DOI: 10.2210/pdb7xib/pdb
• EMDB information: 33201
• Descriptor: DNA (cytosine-5)-methyltransferase 1, DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3'), DNA (5'-D(*CP*CP*TP*TP*CP*(C55)P*GP*TP*AP*AP*GP*T)-3'), ... (5 entities in total)
• Functional Keywords: dna methyltransferase, transferase-dna complex, transferase/dna
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 150641.75

Authors

Onoda, H.,Kikuchi, A.,Kori, S.,Yoshimi, S.,Yamagata, A.,Arita, K. (deposition date: 2022-04-12, release date: 2022-11-30, Last modification date: 2024-07-03)

Primary citation

Kikuchi, A.,Onoda, H.,Yamaguchi, K.,Kori, S.,Matsuzawa, S.,Chiba, Y.,Tanimoto, S.,Yoshimi, S.,Sato, H.,Yamagata, A.,Shirouzu, M.,Adachi, N.,Sharif, J.,Koseki, H.,Nishiyama, A.,Nakanishi, M.,Defossez, P.A.,Arita, K.
Structural basis for activation of DNMT1.
Nat Commun, 13:7130-7130, 2022

PubMed Abstract: DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.

PubMed: 36414620
DOI: 10.1038/s41467-022-34779-4

Experimental method

ELECTRON MICROSCOPY (2.23 Å)