8QE2

Crystal structure of human MAT2a bound to S-Adenosylmethionine and Compound 21

8QE2 の概要

• エントリーDOI: 10.2210/pdb8qe2/pdb
• 分子名称: S-adenosylmethionine synthase isoform type-2, 4-[4-[bis(fluoranyl)methoxy]phenyl]-3-cyclopropyl-6-(2-methylindazol-5-yl)-2~{H}-pyrazolo[4,3-b]pyridin-5-one, S-ADENOSYLMETHIONINE, ... (4 entities in total)
• 機能のキーワード: s-adenosylmethionine biosynthesis, allosteric inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44781.70

構造登録者

Schimpl, M. (登録日: 2023-08-30, 公開日: 2024-03-20, 最終更新日: 2024-04-10)

主引用文献

Atkinson, S.J.,Bagal, S.K.,Argyrou, A.,Askin, S.,Cheung, T.,Chiarparin, E.,Coen, M.,Collie, I.T.,Dale, I.L.,De Fusco, C.,Dillman, K.,Evans, L.,Feron, L.J.,Foster, A.J.,Grondine, M.,Kantae, V.,Lamont, G.M.,Lamont, S.,Lynch, J.T.,Nilsson Lill, S.,Robb, G.R.,Saeh, J.,Schimpl, M.,Scott, J.S.,Smith, J.,Srinivasan, B.,Tentarelli, S.,Vazquez-Chantada, M.,Wagner, D.,Walsh, J.J.,Watson, D.,Williamson, B.
Development of a Series of Pyrrolopyridone MAT2A Inhibitors.
J.Med.Chem., 67:4541-4559, 2024

PubMed Abstract: The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

PubMed: 38466661
DOI: 10.1021/acs.jmedchem.3c01860

実験手法

X-RAY DIFFRACTION (1.109 Å)