Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2

Abstract

The protein tyrosine phosphatase SHP2 is a key regulator of cell cycle control. Here the authors combine NMR measurements and X-ray crystallography and show that wild-type SHP2 dynamically exchanges between a closed inactive conformation and an open activated form and that the oncogenic E76K mutation shifts the equilibrium to the open state, which is reversed by binding of the allosteric inhibitor SHP099.