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Abstract
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.