View source for 7acd


==Crystal structure of the human METTL3-METTL14 complex with compound T30 (UZH1a)==
<StructureSection load='7acd' size='340' side='right'caption='[[7acd]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7acd]] is a 2 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=7ACD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ACD 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=R72:4-[(4,4-dimethylpiperidin-1-yl)methyl]-2-oxidanyl-~{N}-[[(3~{R})-3-oxidanyl-1-[6-[(phenylmethyl)amino]pyrimidin-4-yl]piperidin-3-yl]methyl]benzamide'>R72</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=7acd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7acd OCA], [https://pdbe.org/7acd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7acd RCSB], [https://www.ebi.ac.uk/pdbsum/7acd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7acd ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MTA70_HUMAN MTA70_HUMAN] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> <ref>PMID:25719671</ref> <ref>PMID:25799998</ref> <ref>PMID:26321680</ref> <ref>PMID:26593424</ref> <ref>PMID:9409616</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The methylase METTL3 is the writer enzyme of the N(6) -methyladenosine (m(6) A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose-dependent reduction in the m(6) A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications (i. e., m(1) A, m(6) A(m) , m(7) G), suggesting selectivity of the developed compound towards other RNA methyltransferases.

METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes.,Moroz-Omori EV, Huang D, Kumar Bedi R, Cheriyamkunnel SJ, Bochenkova E, Dolbois A, Rzeczkowski MD, Li Y, Wiedmer L, Caflisch A ChemMedChem. 2021 Oct 6;16(19):3035-3043. doi: 10.1002/cmdc.202100291. Epub 2021 , Jul 29. PMID:34237194<ref>PMID:34237194</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7acd" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bedi RK]]
[[Category: Caflisch A]]
[[Category: Huang D]]