实验导向的分子模拟定义了一个异质的结构组合,用于PTPN11并联SH2域
Michelangelo Marasco1, John Kirkpatrick2, Teresa Carlomagno2,3
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center New York NY USA.
Chemical science
|June 2, 2023
概括
SHP2蛋白质的联SH2域中的结构可塑性对其功能至关重要. 分子模拟揭示了一组异质结构,解释了SHP2如何对刺激做出反应,并使细胞过程的效应因子结合成为可能.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- SHP2蛋白调节细胞过程;它的突变与发育障碍和癌症有关.
- SHP2包括串联的SH2域,一个PTP域和一个C端尾.
- SHP2的激活取决于类与SH2域的结合,其中的方向和间距至关重要.
研究的目的:
- 确定溶液中SHP2的联SH2域的异质结构组合.
- 了解SHP2激活和效应器结合背后的结构动态.
主要方法:
- 实验引导的分子模拟.
- 分析小角度X射线散射 (SAXS) 和NMR残极二极合 (RDC) 数据的分析.
主要成果:
- 该研究确定了合SH2域的溶液结构组合,与实验数据相一致.
- 在N-SH2域中,与C-SH2域相比,N-SH2域表现出不同的方向和位置.
- 这种结构性可塑性被认为是SHP2功能活动的关键.
结论:
- SHP2合SH2域的内在结构可塑性对其功能至关重要.
- 这种可塑性使SHP2能够响应外部刺激并结合效应器.
- 结果提供了关于健康和疾病背景中的SHP2调节的见解.
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