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

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 exchang...

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Autores principales: Pádua, Ricardo A. P., Sun, Yizhi, Marko, Ingrid, Pitsawong, Warintra, Stiller, John B., Otten, Renee, Kern, Dorothee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207724/
https://www.ncbi.nlm.nih.gov/pubmed/30375376
http://dx.doi.org/10.1038/s41467-018-06814-w
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author Pádua, Ricardo A. P.
Sun, Yizhi
Marko, Ingrid
Pitsawong, Warintra
Stiller, John B.
Otten, Renee
Kern, Dorothee
author_facet Pádua, Ricardo A. P.
Sun, Yizhi
Marko, Ingrid
Pitsawong, Warintra
Stiller, John B.
Otten, Renee
Kern, Dorothee
author_sort Pádua, Ricardo A. P.
collection PubMed
description 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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spelling pubmed-62077242018-10-31 Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2 Pádua, Ricardo A. P. Sun, Yizhi Marko, Ingrid Pitsawong, Warintra Stiller, John B. Otten, Renee Kern, Dorothee Nat Commun Article 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. Nature Publishing Group UK 2018-10-30 /pmc/articles/PMC6207724/ /pubmed/30375376 http://dx.doi.org/10.1038/s41467-018-06814-w Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pádua, Ricardo A. P.
Sun, Yizhi
Marko, Ingrid
Pitsawong, Warintra
Stiller, John B.
Otten, Renee
Kern, Dorothee
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
title Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
title_full Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
title_fullStr Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
title_full_unstemmed Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
title_short Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
title_sort mechanism of activating mutations and allosteric drug inhibition of the phosphatase shp2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207724/
https://www.ncbi.nlm.nih.gov/pubmed/30375376
http://dx.doi.org/10.1038/s41467-018-06814-w
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