8VHC

Crystal Structure of Human IDH1 R132Q in complex with NADPH

8VHC の概要

• エントリーDOI: 10.2210/pdb8vhc/pdb
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, GLYCEROL, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 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: 2
• 化学式量合計: 98867.39

構造登録者

Mealka, M.,Sohl, C.D.,Huxford, T. (登録日: 2023-12-31, 公開日: 2024-04-24, 最終更新日: 2024-05-22)

主引用文献

Mealka, M.,Sierra, N.A.,Avellaneda Matteo, D.,Albekioni, E.,Khoury, R.,Mai, T.,Conley, B.M.,Coleman, N.J.,Sabo, K.A.,Komives, E.A.,Bobkov, A.A.,Cooksy, A.L.,Silletti, S.,Schiffer, J.M.,Huxford, T.,Sohl, C.D.
Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
Nat Commun, 15:3785-3785, 2024

PubMed Abstract: Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling reveals a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.

PubMed: 38710674
DOI: 10.1038/s41467-024-48277-2

実験手法

X-RAY DIFFRACTION (2.44 Å)