Imatinib can act as an Allosteric Activator of Abl Kinase |
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| Institution: | 1. Department of Chemistry, University of Waterloo, Waterloo N2L 3G1, Ontario, Canada;2. Bristol Myers Squibb, Cambridge, MA 02140, United States;1. Department of Life Science, Pohang University of Science and Technology, Pohang 37673, South Korea;2. Center for Genomic Integrity Institute for Basic Science (IBS), UNIST, Ulsan 44919, South Korea;3. Department of Biological Sciences & Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08832, South Korea;1. School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia;2. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia;3. Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia;4. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia;5. Ophthalmology, University of Melbourne, Department of Surgery Melbourne, Victoria 3000, Australia;6. Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia;1. Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, MA 02139, United States;2. Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, United States;3. Department of Physics, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, United States;4. Department of Biomedical Engineering, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, United States;1. Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhan Nagar, Kolkata 700064, India;2. High Pressure & Synchrotron Radiation Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India;1. Institute for Molecular Virology, University of Minnesota - Twin Cities, Minneapolis, MN 55455 USA;2. Division of Basic Sciences, School of Dentistry, University of Minnesota - Twin Cities, Minneapolis, MN 55455 USA;3. Masonic Cancer Center, University of Minnesota - Twin Cities, Minneapolis, MN 55455 USA;4. Dept. of Microbiology & Immunology, University of Minnesota - Twin Cities, Minneapolis, MN 55455 USA |
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| 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. |
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