View source for 8cth


==Cryo-EM structure of human METTL1-WDR4-tRNA(Phe) complex==
<StructureSection load='8cth' size='340' side='right'caption='[[8cth]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8cth]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CTH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CTH 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MA:6-HYDRO-1-METHYLADENOSINE-5-MONOPHOSPHATE'>1MA</scene>, <scene name='pdbligand=2MG:2N-METHYLGUANOSINE-5-MONOPHOSPHATE'>2MG</scene>, <scene name='pdbligand=5MC:5-METHYLCYTIDINE-5-MONOPHOSPHATE'>5MC</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene>, <scene name='pdbligand=7MG:7N-METHYL-8-HYDROGUANOSINE-5-MONOPHOSPHATE'>7MG</scene>, <scene name='pdbligand=H2U:5,6-DIHYDROURIDINE-5-MONOPHOSPHATE'>H2U</scene>, <scene name='pdbligand=M2G:N2-DIMETHYLGUANOSINE-5-MONOPHOSPHATE'>M2G</scene>, <scene name='pdbligand=OMG:O2-METHYLGUANOSINE-5-MONOPHOSPHATE'>OMG</scene>, <scene name='pdbligand=PSU:PSEUDOURIDINE-5-MONOPHOSPHATE'>PSU</scene>, <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=8cth FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cth OCA], [https://pdbe.org/8cth PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cth RCSB], [https://www.ebi.ac.uk/pdbsum/8cth PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cth ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TRMB_HUMAN TRMB_HUMAN] Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA.<ref>PMID:12403464</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Chemical modifications of RNA have key roles in many biological processes(1-3). N(7)-methylguanosine (m(7)G) is required for integrity and stability of a large subset of tRNAs(4-7). The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types(8-14). Mutations in WDR4 cause human developmental phenotypes including microcephaly(15-17). How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive(18). Here we show, through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the alphaC region of METTL1 transforms into a helix, which together with the alpha6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.

Structural basis of regulated m(7)G tRNA modification by METTL1-WDR4.,Li J, Wang L, Hahn Q, Nowak RP, Viennet T, Orellana EA, Roy Burman SS, Yue H, Hunkeler M, Fontana P, Wu H, Arthanari H, Fischer ES, Gregory RI Nature. 2023 Jan;613(7943):391-397. doi: 10.1038/s41586-022-05566-4. Epub 2023 , Jan 4. PMID:36599985<ref>PMID:36599985</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8cth" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Saccharomyces cerevisiae]]
[[Category: Fishcer ES]]
[[Category: Fontana P]]
[[Category: Gregory RI]]
[[Category: Hunkeler M]]
[[Category: Li J]]
[[Category: Roy-Burman SS]]
[[Category: Wang L]]
[[Category: Wu H]]