Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire.
Department of Chemical Engineering, University of New Hampshire, Durham, New Hampshire.
Biophys J. 2021 Feb 2;120(3):517-526. doi: 10.1016/j.bpj.2020.12.010. Epub 2020 Dec 19.
Regulators of G-protein signaling (RGS) proteins play a central role in modulating signaling via G-protein coupled receptors (GPCRs). Specifically, RGS proteins bind to activated Gα subunits in G-proteins, accelerate the GTP hydrolysis, and thereby rapidly dampen GPCR signaling. Therefore, covalent molecules targeting conserved cysteine residues among RGS proteins have emerged as potential candidates to inhibit the RGS/Gα protein-protein interaction and enhance GPCR signaling. Although these inhibitors bind to conserved cysteine residues among RGS proteins, we have previously suggested [J. Am. Chem. Soc. 2018;140:3454-3460] that their potencies and specificities are related to differential protein dynamics among RGS proteins. Using data from all-atom molecular dynamics simulations, we reveal these differences in dynamics of RGS proteins by partitioning the protein structural space into a network of communities that allow allosteric signals to propagate along unique pathways originating at inhibitor binding sites and terminating at the RGS/Gα protein-protein interface.
G 蛋白信号调节蛋白（RGS）在调节 G 蛋白偶联受体（GPCR）信号转导中起着核心作用。具体来说，RGS 蛋白与 G 蛋白中激活的 Gα 亚基结合，加速 GTP 水解，从而迅速抑制 GPCR 信号转导。因此，靶向 RGS 蛋白中保守半胱氨酸残基的共价分子已成为抑制 RGS/Gα 蛋白-蛋白相互作用和增强 GPCR 信号转导的潜在候选物。尽管这些抑制剂与 RGS 蛋白中的保守半胱氨酸残基结合，但我们之前曾提出 [J. Am. Chem. Soc. 2018;140:3454-3460]，它们的效力和特异性与 RGS 蛋白之间的差异蛋白动力学有关。我们使用来自全原子分子动力学模拟的数据，通过将蛋白质结构空间划分为社区网络来揭示 RGS 蛋白在动力学上的差异，该网络允许变构信号沿着起源于抑制剂结合位点并终止于 RGS/Gα 蛋白-蛋白界面的独特途径传播。
