title: A Src-like inactive conformation in the abl tyrosine kinase domain.
abstract: 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 180 degrees 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 with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.
authors.affiliation: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Levinson
authors.forename: Olga
authors.initials: O
authors.lastname: Kuchment
authors.forename: Kui
authors.initials: K
authors.lastname: Shen
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Young
authors.forename: Michael
authors.initials: M
authors.lastname: Koldobskiy
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D001665:Binding Sites; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases