7PJN
Crystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and inhibitor DS-1001B
Summary for 7PJN
| Entry DOI | 10.2210/pdb7pjn/pdb |
| Descriptor | Isocitrate dehydrogenase [NADP] cytoplasmic, (E)-3-(1-(5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)isoxazole-4-carbonyl)-3-methyl-1H-indol-4-yl)acrylic acid, CITRIC ACID, ... (7 entities in total) |
| Functional Keywords | oxidoreductase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 197859.61 |
| Authors | Reinbold, R.,Rabe, P.,Abboud, M.I.,Schofield, C.J.,Clifton, I.J. (deposition date: 2021-08-24, release date: 2022-07-13, Last modification date: 2024-10-09) |
| Primary citation | Reinbold, R.,Hvinden, I.C.,Rabe, P.,Herold, R.A.,Finch, A.,Wood, J.,Morgan, M.,Staudt, M.,Clifton, I.J.,Armstrong, F.A.,McCullagh, J.S.O.,Redmond, J.,Bardella, C.,Abboud, M.I.,Schofield, C.J. Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Nat Commun, 13:4785-4785, 2022 Cited by PubMed Abstract: Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials. PubMed: 35970853DOI: 10.1038/s41467-022-32436-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.45 Å) |
Structure validation
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