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7bhu

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<StructureSection load='7bhu' size='340' side='right'caption='[[7bhu]], [[Resolution|resolution]] 1.15&Aring;' scene=''>
<StructureSection load='7bhu' size='340' side='right'caption='[[7bhu]], [[Resolution|resolution]] 1.15&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7bhu]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BHU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7bhu]] is a 1 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=7BHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BHU FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=TOW:7-chloranyl-4-(dimethylamino)-1-(2-hydroxyethyl)quinazolin-2-one'>TOW</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.15&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=TOW:7-chloranyl-4-(dimethylamino)-1-(2-hydroxyethyl)quinazolin-2-one'>TOW</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=7bhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bhu OCA], [https://pdbe.org/7bhu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bhu RCSB], [https://www.ebi.ac.uk/pdbsum/7bhu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bhu ProSAT]</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=7bhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bhu OCA], [https://pdbe.org/7bhu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bhu RCSB], [https://www.ebi.ac.uk/pdbsum/7bhu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bhu ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/METK2_HUMAN METK2_HUMAN]] Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
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[https://www.uniprot.org/uniprot/METK2_HUMAN METK2_HUMAN] Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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==See Also==
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*[[S-adenosylmethionine synthetase 3D structures|S-adenosylmethionine synthetase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7bhu" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Methionine adenosyltransferase]]
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[[Category: Argyrou A]]
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[[Category: Argyrou, A]]
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[[Category: Bagal S]]
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[[Category: Bagal, S]]
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[[Category: Borjesson U]]
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[[Category: Borjesson, U]]
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[[Category: Cheung T]]
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[[Category: Cheung, T]]
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[[Category: Chiarparin E]]
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[[Category: Chiarparin, E]]
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[[Category: Collie I]]
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[[Category: Collie, I]]
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[[Category: De Fusco C]]
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[[Category: Evans, L]]
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[[Category: Evans L]]
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[[Category: Fusco, C De]]
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[[Category: Grondine M]]
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[[Category: Grondine, M]]
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[[Category: Narasimhan P]]
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[[Category: Narasimhan, P]]
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[[Category: Robb G]]
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[[Category: Robb, G]]
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[[Category: Schimpl M]]
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[[Category: Schimpl, M]]
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[[Category: Scott JS]]
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[[Category: Scott, J S]]
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[[Category: Stubbs C]]
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[[Category: Stubbs, C]]
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[[Category: Tentarelli S]]
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[[Category: Tentarelli, S]]
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[[Category: Underwood E]]
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[[Category: Underwood, E]]
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[[Category: Vazquez-Chantada M]]
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[[Category: Vazquez-Chantada, M]]
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[[Category: Wagner DJ]]
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[[Category: Wagner, D J]]
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[[Category: Allosteric inhibitor]]
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[[Category: Fragment-based drug design]]
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[[Category: Oncology]]
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[[Category: Synthetic lethal therapy]]
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[[Category: Transferase]]
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Current revision

Crystal structure of MAT2a with elaborated fragment 26 bound in the allosteric site

PDB ID 7bhu

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