View source for 7bhr


==Crystal structure of MAT2a with triazinone fragment 1 bound in the allosteric site==
<StructureSection load='7bhr' size='340' side='right'caption='[[7bhr]], [[Resolution|resolution]] 1.08&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7bhr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BHR FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=TQE:4-(dimethylamino)-6-ethoxy-1~{H}-1,3,5-triazin-2-one'>TQE</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Methionine_adenosyltransferase Methionine adenosyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.6 2.5.1.6] </span></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=7bhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bhr OCA], [https://pdbe.org/7bhr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bhr RCSB], [https://www.ebi.ac.uk/pdbsum/7bhr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bhr ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/METK2_HUMAN METK2_HUMAN]] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model.,De Fusco C, Schimpl M, Borjesson U, Cheung T, Collie I, Evans L, Narasimhan P, Stubbs C, Vazquez-Chantada M, Wagner DJ, Grondine M, Sanders MG, Tentarelli S, Underwood E, Argyrou A, Smith JM, Lynch JT, Chiarparin E, Robb G, Bagal SK, Scott JS J Med Chem. 2021 Apr 26. doi: 10.1021/acs.jmedchem.1c00067. PMID:33900758<ref>PMID:33900758</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7bhr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Methionine adenosyltransferase]]
[[Category: Argyrou, A]]
[[Category: Bagal, S]]
[[Category: Borjesson, U]]
[[Category: Cheung, T]]
[[Category: Chiarparin, E]]
[[Category: Collie, I]]
[[Category: Evans, L]]
[[Category: Fusco, C De]]
[[Category: Grondine, M]]
[[Category: Narasimhan, P]]
[[Category: Robb, G]]
[[Category: Schimpl, M]]
[[Category: Scott, J S]]
[[Category: Stubbs, C]]
[[Category: Tentarelli, S]]
[[Category: Underwood, E]]
[[Category: Vazquez-Chantada, M]]
[[Category: Wagner, D J]]
[[Category: Allosteric inhibitor]]
[[Category: Fragment-based drug design]]
[[Category: Oncology]]
[[Category: Synthetic lethal therapy]]
[[Category: Transferase]]