Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Ricardo A. P. Pádua, Yizhi Sun, Ingrid Marko, Warintra Pitsawong, John B. Stiller, Renee Otten, Dorothee Kern

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. More... »

PAGES

4507

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-06814-w

    DOI

    http://dx.doi.org/10.1038/s41467-018-06814-w

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1107829087

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30375376


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