7N9G
Crystal structure of the Abl 1b Kinase domain in complex with Dasatinib and Imatinib
Summary for 7N9G
| Entry DOI | 10.2210/pdb7n9g/pdb |
| Descriptor | Tyrosine-protein kinase ABL1, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE, ... (5 entities in total) |
| Functional Keywords | abl kinase, kinase allosteric regulation, drug resistance, cell cycle |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 3 |
| Total formula weight | 97516.01 |
| Authors | Miller, D.J.,Xie, T. (deposition date: 2021-06-17, release date: 2022-04-27, Last modification date: 2023-10-18) |
| Primary citation | Xie, T.,Saleh, T.,Rossi, P.,Miller, D.,Kalodimos, C.G. Imatinib can act as an Allosteric Activator of Abl Kinase. J.Mol.Biol., 434:167349-167349, 2022 Cited by PubMed Abstract: Imatinib is an ATP-competitive inhibitor of Bcr-Abl kinase and the first drug approved for chronic myelogenous leukemia (CML) treatment. Here we show that imatinib binds to a secondary, allosteric site located in the myristoyl pocket of Abl to function as an activator of the kinase activity. Abl transitions between an assembled, inhibited state and an extended, activated state. The equilibrium is regulated by the conformation of the αΙ helix, which is located nearby the allosteric pocket. Imatinib binding to the allosteric pocket elicits an αΙ helix conformation that is not compatible with the assembled state, thereby promoting the extended state and stimulating the kinase activity. Although in wild-type Abl the catalytic pocket has a much higher affinity for imatinib than the allosteric pocket does, the two binding affinities are comparable in Abl variants carrying imatinib-resistant mutations in the catalytic site. A previously isolated imatinib-resistant mutation in patients appears to be mediating its function by increasing the affinity of imatinib for the allosteric pocket, providing a hitherto unknown mechanism of drug resistance. Our results highlight the benefit of combining imatinib with allosteric inhibitors to maximize their inhibitory effect on Bcr-Abl. PubMed: 34774565DOI: 10.1016/j.jmb.2021.167349 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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