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

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 mutatio...

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Main Authors:	Ricardo A. P. Pádua, Yizhi Sun, Ingrid Marko, Warintra Pitsawong, John B. Stiller, Renee Otten, Dorothee Kern
Format:	Article
Language:	English
Published:	Nature Publishing Group 2018-10-01
Series:	Nature Communications
Online Access:	https://doi.org/10.1038/s41467-018-06814-w

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spelling	doaj-77cc04b8724e47ce9663728a803fea112021-05-11T10:29:03ZengNature Publishing GroupNature Communications2041-17232018-10-019111410.1038/s41467-018-06814-wMechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2Ricardo A. P. Pádua0Yizhi Sun1Ingrid Marko2Warintra Pitsawong3John B. Stiller4Renee Otten5Dorothee Kern6Howard Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityHoward Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityHoward Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityHoward Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityHoward Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityHoward Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityHoward Hughes Medical Institute, Department of Biochemistry, Brandeis UniversityThe 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.https://doi.org/10.1038/s41467-018-06814-w
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Ricardo A. P. Pádua Yizhi Sun Ingrid Marko Warintra Pitsawong John B. Stiller Renee Otten Dorothee Kern
spellingShingle	Ricardo A. P. Pádua Yizhi Sun Ingrid Marko Warintra Pitsawong John B. Stiller Renee Otten Dorothee Kern Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2 Nature Communications
author_facet	Ricardo A. P. Pádua Yizhi Sun Ingrid Marko Warintra Pitsawong John B. Stiller Renee Otten Dorothee Kern
author_sort	Ricardo A. P. Pádua
title	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_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_sort	mechanism of activating mutations and allosteric drug inhibition of the phosphatase shp2
publisher	Nature Publishing Group
series	Nature Communications
issn	2041-1723
publishDate	2018-10-01
description	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.
url	https://doi.org/10.1038/s41467-018-06814-w
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Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2

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