Issue 7, 2023

How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2

Abstract

Protein tyrosine phosphatase SHP2 is a key regulator modulating several signaling pathways. The oncogenic mutation E76K in SHP2 releases the enzyme from an autoinhibited, closed conformation into an active, open conformation. Here, we investigated the conformational dynamics of SHP2 and the effect of the E76K mutation on its conformational ensemble via extensive molecular dynamics (MD) and metadynamics (MetaD) simulations. Our simulations provide atomistic details on how the E76K mutated SHP2 prefers the open state and also reveal that the transition between the closed and the open states is highly collective. Several intermediate metastable states during the conformational transition between the closed and the open states were also investigated. Understanding how the single E76K mutation induces the conformational change in SHP2 could facilitate the further design of SHP2 inhibitors.

Graphical abstract: How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2

Supplementary files

Article information

Article type
Paper
Submitted
24 Nov. 2022
Accepted
23 Janv. 2023
First published
01 Febr. 2023
This article is Open Access
Creative Commons BY license

RSC Adv., 2023,13, 4263-4274

How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2

Y. Hou, X. Lu, Z. Xu, J. Qu and J. Huang, RSC Adv., 2023, 13, 4263 DOI: 10.1039/D2RA07472A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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