title: The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation.
abstract: The regulation of the activity of Abl and Src family tyrosine kinases is mediated by intramolecular interactions between the SH3, SH2, and kinase (SH1) domains. We have determined the crystal structure of an unphosphorylated form of c-Src in which the SH2 domain is not bound to the C-terminal tail. This results in an open structure where the kinase domain adopts an active conformation and the C terminus binds within a hydrophobic pocket in the C-terminal lobe. NMR binding studies support the hypothesis that an N-terminal myristate could bind in this pocket, as observed for Abl, suggesting that c-Src may also be regulated by myristate binding. In addition, the structure contains a des-methyl analog of the antileukemia drug imatinib (STI571; Gleevec). This structure reveals why the drug shows a low affinity for active kinase conformations, contributing to its excellent kinase selectivity profile.
authors.affiliation: Discovery Technologies, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. sandra.jacob@novartis.com
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fendrich
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Janis
authors.initials: J
authors.lastname: Liebetanz
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
mesh_terms: D000595:Amino Acid Sequence; D001549:Benzamides; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D007930:Leucine / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019814:Myristic Acid / Q000737:chemistry / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019814:Myristic Acid; D014443:Tyrosine; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D007930:Leucine