J. Biol. Chem., Vol. 283, Issue 26, 99930, June 27, 2008
ABL Bodied Structures
The ABL protein kinase is an important drug target in the treatment of chronic myelogenous leukemia (in the form of the oncogenic BCR-ABL fusion protein). However, current structural understanding of ABL and other kinases is largely based on x-ray crystallography of the solid state that may not capture the full ensemble of conformations available in solution. In this Paper of the Week, Navratna Vajpai and colleagues present NMR structures of the ABL kinase in complex with three clinically used drugs (imatinib, nilotinib, and dasatinib), providing the first detailed solution structures of a kinase-inhibitor complex. These structures provide insights into the structural dynamics of ABL protein kinase and help clarify its physiologically relevant binding modes. For example, residual dipolar coupling (RDC) data on the imatinib and nilotinib complexes show that the ABL activation loop adopts the inactive conformation, whereas the dasatinib complex preserves the active conformation, contrary to the predictions based upon molecular modeling. These structures will enhance our understanding of multiple inactive conformations observed in some kinases and may also shed light on how point mutations in BCR-ABL lead to drug resistance, enabling the rationale design of more potent inhibitors.
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Ribbon diagram of ABL kinase bound with the inhibitor nilotinib (in green).
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FOOTNOTES
See referenced article, J. Biol. Chem. 2008, 283, 18292-18302 
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Copyright © 2008 by the American Society for Biochemistry and Molecular Biology.
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