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

  • Nat Commun. 2018 Oct 30;9(1):4507. doi: 10.1038/s41467-018-06814-w.
Ricardo A P Pádua  1 ,  Yizhi Sun  1  2 ,  Ingrid Marko  1 ,  Warintra Pitsawong  1 ,  John B Stiller  1 ,  Renee Otten  1 ,  Dorothee Kern  3
Affiliations
  • 1. Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, MA, 02454, USA.
  • 2. Department of Cancer Biology and Cell Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02215, USA.
  • 3. Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, MA, 02454, USA. [email protected].
PMID: 30375376 DOI: 10.1038/s41467-018-06814-w
Abstract

Protein tyrosine Phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K's much higher activity, demands significantly greater SHP099 concentrations to restore wild-type activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants.

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