View source for 8tdr


==Crystal structure of the methyltransferase domain of DNMT3A homotetramer==
<StructureSection load='8tdr' size='340' side='right'caption='[[8tdr]], [[Resolution|resolution]] 3.32&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8tdr]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8TDR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TDR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.32&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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=8tdr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tdr OCA], [https://pdbe.org/8tdr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tdr RCSB], [https://www.ebi.ac.uk/pdbsum/8tdr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tdr ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DNM3A_HUMAN DNM3A_HUMAN] Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. Plays a role in paternal and maternal imprinting. Required for methylation of most imprinted loci in germ cells. Acts as a transcriptional corepressor for ZNF238. Can actively repress transcription through the recruitment of HDAC activity (By similarity).<ref>PMID:16357870</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.,Lu J, Guo Y, Yin J, Chen J, Wang Y, Wang GG, Song J Nat Commun. 2024 Apr 10;15(1):3111. doi: 10.1038/s41467-024-47398-y. PMID:38600075<ref>PMID:38600075</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8tdr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lu JW]]
[[Category: Song JK]]