View source for 7kce


==Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 2==
<StructureSection load='7kce' size='340' side='right'caption='[[7kce]], [[Resolution|resolution]] 1.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7kce]] 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=7KCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KCE 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]] 1.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=J41:5-methyl-2,3-diphenylpyrazolo[1,5-a]pyrimidin-7(4H)-one'>J41</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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=7kce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kce OCA], [https://pdbe.org/7kce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kce RCSB], [https://www.ebi.ac.uk/pdbsum/7kce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kce 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 ==
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled &gt;10000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).

Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion.,Konteatis Z, Travins J, Gross S, Marjon K, Barnett A, Mandley E, Nicolay B, Nagaraja R, Chen Y, Sun Y, Liu Z, Yu J, Ye Z, Jiang F, Wei W, Fang C, Gao Y, Kalev P, Hyer ML, DeLaBarre B, Jin L, Padyana AK, Dang L, Murtie J, Biller SA, Sui Z, Marks KM J Med Chem. 2021 Apr 8. doi: 10.1021/acs.jmedchem.0c01895. PMID:33829783<ref>PMID:33829783</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7kce" style="background-color:#fffaf0;"></div>

==See Also==
*[[S-adenosylmethionine synthetase 3D structures|S-adenosylmethionine synthetase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jin L]]
[[Category: Padyana A]]