The Src kinases are proteins produced by the Src proto-oncogene.
Autoinhibition of the Src kinases has long been known to depend on an intramolecular
interaction between a
phosphotyrosine-binding module known as the SH2 (Src-homology 2) domain, located within these proteins before the catalytic kinase domain, and a C-terminal phosphotyrosine residue (Tyr 527). The first structures of
the inactive forms of the Src kinases Hck (determined by our group) and c-Src (determined by Stephen Harrison, HHMI,
Harvard University, and his coworkers) revealed an architecture that was surprising, because the internal
engagement of the SH2 domain by phosphorylated Tyr 527 occurs on the distal surface of the catalytic domain of the
kinase, about 40 Å from the catalytic center. Neither the SH2 domain nor the SH3 domain (another modular binding
domain present in the Src kinases) blocks the active site directly, leaving the mechanism of inhibition by these
domains somewhat of a mystery. This page describes our intial work on the Src kinase Hck.
We later analysed Hck at higher resolution, bound to the inhibitor PP1. This work revealed a role for the activation loop in the auto-inhibition mechanism, which was not fully recognized in this earlier analyisis (Steve Harrison's group found the same thing for c-Src).
More recently, molecular dynamics
analysis showed a role for the SH2-SH3 connector in mediating the effect of