Solution Conformations and Dynamics of ABL Kinase-Inhibitor Complexes Determined by NMR Substantiate the Different Binding Modes of Imatinib/Nilotinib and Dasatinib

Current structural understanding of kinases is largely based on x-ray crystallographic studies, whereas very little data exist on the conformations and dynamics that kinases adopt in the solution state. ABL kinase is an important drug target in the treatment of chronic myelogenous leukemia. Here, we...

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Published inThe Journal of biological chemistry Vol. 283; no. 26; pp. 18292 - 18302
Main Authors Vajpai, Navratna, Strauss, André, Fendrich, Gabriele, Cowan-Jacob, Sandra W., Manley, Paul W., Grzesiek, Stephan, Jahnke, Wolfgang
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 27.06.2008
American Society for Biochemistry and Molecular Biology
Subjects
Amino Acid Sequence
Antineoplastic Agents - pharmacology
Benzamides
Chemistry, Pharmaceutical - methods
Dasatinib
Drug Design
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Imatinib Mesylate
Magnetic Resonance Spectroscopy - methods
Models, Molecular
Molecular Conformation
Molecular Sequence Data
Piperazines - pharmacology
Protein Conformation
Proto-Oncogene Proteins c-abl - chemistry
Pyrimidines - pharmacology
Thiazoles - pharmacology
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Summary:Current structural understanding of kinases is largely based on x-ray crystallographic studies, whereas very little data exist on the conformations and dynamics that kinases adopt in the solution state. ABL kinase is an important drug target in the treatment of chronic myelogenous leukemia. Here, we present the first characterization of ABL kinase in complex with three clinical inhibitors (imatinib, nilotinib, and dasatinib) by modern solution NMR techniques. Structural and dynamical results were derived from complete backbone resonance assignments, experimental residual dipolar couplings, and 15N relaxation data. Residual dipolar coupling data on the imatinib and nilotinib complexes show that the activation loop adopts the inactive conformation, whereas the dasatinib complex preserves the active conformation, which does not support contrary predictions based upon molecular modeling. Nanosecond as well as microsecond dynamics can be detected for certain residues in the activation loop in the inactive and active conformation complexes.
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ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M801337200