5SVF

IDH1 R132H in complex with IDH125

Summary for 5SVF

• Entry DOI: 10.2210/pdb5svf/pdb
• Related: 5SUN 5SVN 5SVO
• Descriptor: 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)
• Functional Keywords: isocitrate dehydrogenase, rossmann fold, nadph, inhibitor, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : O75874
• Total number of polymer chains: 4
• Total formula weight: 192693.22

Authors

Xie, X.,Kulathila, R. (deposition date: 2016-08-05, release date: 2017-02-08, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.34 Å)