5SVF

IDH1 R132H in complex with IDH125

5SVF の概要

• エントリーDOI: 10.2210/pdb5svf/pdb
• 関連するPDBエントリー: 5SUN 5SVN 5SVO
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (4S)-3-(2-{[(1S)-1-phenylethyl]amino}pyrimidin-4-yl)-4-(propan-2-yl)-1,3-oxazolidin-2-one, ... (5 entities in total)
• 機能のキーワード: isocitrate dehydrogenase, rossmann fold, nadph, inhibitor, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : O75874
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 192693.22

構造登録者

Xie, X.,Kulathila, R. (登録日: 2016-08-05, 公開日: 2017-02-08, 最終更新日: 2024-03-06)

主引用文献

Xie, X.,Baird, D.,Bowen, K.,Capka, V.,Chen, J.,Chenail, G.,Cho, Y.,Dooley, J.,Farsidjani, A.,Fortin, P.,Kohls, D.,Kulathila, R.,Lin, F.,McKay, D.,Rodrigues, L.,Sage, D.,Toure, B.B.,van der Plas, S.,Wright, K.,Xu, M.,Yin, H.,Levell, J.,Pagliarini, R.A.
Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity.
Structure, 25:506-513, 2017

PubMed Abstract: Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1 mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

PubMed: 28132785
DOI: 10.1016/j.str.2016.12.017

実験手法

X-RAY DIFFRACTION (2.34 Å)