a src-like inactive conformation in the abl tyrosine kinase domainsrc-like活性构象的abl酪氨酸激酶域.pdfVIP

PLoS BIOLOGY A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain 1,2,3[ 1,2,3[ 4 1,2,3¤ 4 Nicholas M. Levinson , Olga Kuchment , Kui Shen , Matthew A. Young , Michael Koldobskiy , Martin Karplus5 4 1,2,3,6* , Philip A. Cole , John Kuriyan 1 Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, United States of America, 2 Department of Chemistry, University of California Berkeley, Berkeley, California, United States of America, 3 Howard Hughes Medical Institute, University of California Berkeley, Berkeley, California, United States of America, 4 Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 5 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America, 6 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 1808 with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex wit