View source for 7xib


==Cryo-EM structure of human DNMT1 (aa:351-1616) in complex with ubiquitinated H3 and hemimethylated DNA analog (CXXC-disordered form)==
<StructureSection load='7xib' size='340' side='right'caption='[[7xib]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xib]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XIB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.23&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5CM:5-METHYL-2-DEOXY-CYTIDINE-5-MONOPHOSPHATE'>5CM</scene>, <scene name='pdbligand=EIX:[(2R,3S,5S)-5-[(4R,5R)-6-azanyl-5-fluoranyl-5-methyl-2-oxidanylidene-4-sulfanyl-4H-pyrimidin-3-yl]-3-oxidanyl-oxolan-2-yl]methyl+dihydrogen+phosphate'>EIX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7xib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xib OCA], [https://pdbe.org/7xib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xib RCSB], [https://www.ebi.ac.uk/pdbsum/7xib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xib ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DNMT1_HUMAN DNMT1_HUMAN] Defects in DNMT1 are the cause of hereditary sensory neuropathy type 1E (HSN1E) [MIM:[https://omim.org/entry/614116 614116]. A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia.<ref>PMID:21532572</ref> 
== Function ==
[https://www.uniprot.org/uniprot/DNMT1_HUMAN DNMT1_HUMAN] Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9.<ref>PMID:16357870</ref> <ref>PMID:18754681</ref> <ref>PMID:18413740</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 alpha-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.

Structural basis for activation of DNMT1.,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 PA, Arita K Nat Commun. 2022 Nov 21;13(1):7130. doi: 10.1038/s41467-022-34779-4. PMID:36414620<ref>PMID:36414620</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7xib" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Arita K]]
[[Category: Kikuchi A]]
[[Category: Kori S]]
[[Category: Onoda H]]
[[Category: Yamagata A]]
[[Category: Yoshimi S]]