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

Ricardo A. P. Pádua, Yizhi Sun, Ingrid Marko, Warintra Pitsawong, John B. Stiller, Renee Otten and Dorothee Kern ()
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Ricardo A. P. Pádua: Brandeis University
Yizhi Sun: Brandeis University
Ingrid Marko: Brandeis University
Warintra Pitsawong: Brandeis University
John B. Stiller: Brandeis University
Renee Otten: Brandeis University
Dorothee Kern: Brandeis University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06814-w

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