8T7D

Crystal structure of wild type IDH1 bound to compound 1

8T7D の概要

• エントリーDOI: 10.2210/pdb8t7d/pdb
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, N-(4-tert-butylphenyl)-7,8-dimethyl-5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepine-6-carboxamide (2 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 193872.67

構造登録者

Lu, J.,Abeywickrema, P.,Heo, M.R.,Parthasarathy, G.,McCoy, M.,Soisson, S.M. (登録日: 2023-06-20, 公開日: 2024-08-28, 最終更新日: 2025-03-12)

主引用文献

McCoy, M.A.,Lu, J.,Richard Miller, F.,Soisson, S.M.,Lam, M.H.,Fischer, C.
Biostructural, biochemical and biophysical studies of mutant IDH1.
Nat Commun, 15:7877-7877, 2024

PubMed Abstract: We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.

PubMed: 39251618
DOI: 10.1038/s41467-024-51692-0

実験手法

X-RAY DIFFRACTION (3.444 Å)