8OOG

Crystal structure of human MAT2a with S-Adenosylmethionine and a fragment bound in a novel pocket

8OOG の概要

• エントリーDOI: 10.2210/pdb8oog/pdb
• 分子名称: S-adenosylmethionine synthase isoform type-2, S-ADENOSYLMETHIONINE, 6-oxidanyl-1,3-benzoxathiol-2-one, ... (5 entities in total)
• 機能のキーワード: methionine adenosyltransferase, s-adenosylmethionine synthetase, fragment screen, allosteric binder, 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: 44658.70

構造登録者

Schimpl, M. (登録日: 2023-04-05, 公開日: 2023-07-12, 最終更新日: 2024-06-19)

主引用文献

La Sala, G.,Pfleger, C.,Kack, H.,Wissler, L.,Nevin, P.,Bohm, K.,Janet, J.P.,Schimpl, M.,Stubbs, C.J.,De Vivo, M.,Tyrchan, C.,Hogner, A.,Gohlke, H.,Frolov, A.I.
Combining structural and coevolution information to unveil allosteric sites.
Chem Sci, 14:7057-7067, 2023

PubMed Abstract: Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets.

PubMed: 37389247
DOI: 10.1039/d2sc06272k

実験手法

X-RAY DIFFRACTION (1.384 Å)