8VHE
Crystal Structure of Human IDH1 R132Q in Complex with NADPH-TCEP Adduct
This is a non-PDB format compatible entry.
Summary for 8VHE
| Entry DOI | 10.2210/pdb8vhe/pdb |
| Descriptor | Isocitrate dehydrogenase [NADP] cytoplasmic, 3,3',3''-({(4R)-1-[(2R,3R,4S,5R)-5-({[(S)-{[(S)-{[(2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-3-hydroxy-4-(phosphonooxy)oxolan-2-yl]methoxy}(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]oxy}methyl)-3,4-dihydroxyoxolan-2-yl]-3-carbamoyl-1,4-dihydropyridin-4-yl}-lambda~5~-phosphanetriyl)tripropanoic acid, GLYCEROL, ... (7 entities in total) |
| Functional Keywords | oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 199288.11 |
| Authors | Mealka, M.,Sohl, C.D.,Huxford, T. (deposition date: 2023-12-31, release date: 2024-04-24, Last modification date: 2024-05-22) |
| Primary citation | 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 Cited by 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: 38710674DOI: 10.1038/s41467-024-48277-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.16 Å) |
Structure validation
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