Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
| Autor: | Warintra Pitsawong, Yizhi Sun, Renee Otten, Ricardo A.P. de Pádua, Ingrid Marko, John B. Stiller, Dorothee Kern |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Magnetic Resonance Spectroscopy Protein Conformation Science Allosteric regulation Phosphatase Mutant Regulator General Physics and Astronomy Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein tyrosine phosphatase Crystallography X-Ray medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Protein structure Allosteric Regulation Piperidines Hydrolase medicine Humans lcsh:Science Mutation Multidisciplinary Chemistry General Chemistry Pyrimidines 030104 developmental biology Biophysics lcsh:Q |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-06814-w |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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