7kdb

Crystal structure of human methionine adenosyltransferase 2A (MAT2A) in complex with SAM and allosteric inhibitor compound 35

spinqualitylabelsall models 7kdb, resolution 1.24Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7kdb is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.24Å Ligands: CL, EDO, GOL, SAM, TRS, WBS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function METK2_HUMAN Catalyzes the formation of S-adenosylmethionine from methionine and ATP. 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 >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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also S-adenosylmethionine synthetase 3D structures

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