Xu W, Doshi A, Lei M, Eck M J, Harrison S C
Laboratory of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115, USA.
Mol Cell. 1999 May;3(5):629-38. doi: 10.1016/s1097-2765(00)80356-1.
Src family kinases are maintained in an assembled, inactive conformation by intramolecular interactions of their SH2 and SH3 domains. Full catalytic activity requires release of these restraints as well as phosphorylation of Tyr-416 in the activation loop. In previous structures of inactive Src kinases, Tyr-416 and flanking residues are disordered. We report here four additional c-Src structures in which this segment adopts an ordered but inhibitory conformation. The ordered activation loop forms an alpha helix that stabilizes the inactive conformation of the kinase domain, blocks the peptide substrate-binding site, and prevents Tyr-416 phosphorylation. Disassembly of the regulatory domains, induced by SH2 or SH3 ligands, or by dephosphorylation of Tyr-527, could lead to exposure and phosphorylation of Tyr-416.
Src家族激酶通过其SH2和SH3结构域的分子内相互作用维持在组装的无活性构象中。完全催化活性需要解除这些限制以及激活环中Tyr-416的磷酸化。在无活性Src激酶的先前结构中，Tyr-416及其侧翼残基是无序的。我们在此报告另外四种c-Src结构，其中该片段采用有序但抑制性的构象。有序的激活环形成一个α螺旋，稳定激酶结构域的无活性构象，阻断肽底物结合位点，并阻止Tyr-416磷酸化。由SH2或SH3配体诱导的调节结构域的解离，或Tyr-527的去磷酸化，可能导致Tyr-416的暴露和磷酸化。
