View source for 6ttv


==Crystal structure of the human METTL3-METTL14 complex bound to Compound 3 (ASI_M3M_138)==
<StructureSection load='6ttv' size='340' side='right'caption='[[6ttv]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ttv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TTV OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TTV FirstGlance]. <br>
</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=NWW:(2~{S},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolane-2-carboxamide'>NWW</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">METTL3, MTA70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), METTL14, KIAA1627 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/mRNA_m(6)A_methyltransferase mRNA m(6)A methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.348 2.1.1.348] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ttv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ttv OCA], [http://pdbe.org/6ttv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ttv RCSB], [http://www.ebi.ac.uk/pdbsum/6ttv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ttv ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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>  [[http://www.uniprot.org/uniprot/MET14_HUMAN MET14_HUMAN]] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. 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 and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. 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 (By similarity).[UniProtKB:Q3UIK4]<ref>PMID:24316715</ref> <ref>PMID:24407421</ref> <ref>PMID:25719671</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N(6) atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.

Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.,Bedi RK, Huang D, Eberle SA, Wiedmer L, Sledz P, Caflisch A ChemMedChem. 2020 May 6;15(9):744-748. doi: 10.1002/cmdc.202000011. Epub 2020 Mar, 23. PMID:32159918<ref>PMID:32159918</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ttv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Bedi, R K]]
[[Category: Caflisch, A]]
[[Category: Huang, D]]
[[Category: Sledz, P]]
[[Category: Complex]]
[[Category: Compound]]
[[Category: Epitranscriptomic]]
[[Category: Mettl14]]
[[Category: Mettl3]]
[[Category: Transferase]]