Soundararajan Meera, Willard Francis S, Kimple Adam J, Turnbull Andrew P, Ball Linda J, Schoch Guillaume A, Gileadi Carina, Fedorov Oleg Y, Dowler Elizabeth F, Higman Victoria A, Hutsell Stephanie Q, Sundström Michael, Doyle Declan A, Siderovski David P
Structural Genomics Consortium, Oxford University, Oxford OX3 7DQ, United Kingdom.
Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6457-62. doi: 10.1073/pnas.0801508105. Epub 2008 Apr 23.
Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Galpha subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Galpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Galpha, RGS domain binding consequently accelerates Galpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Galpha substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential Galpha selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/Galpha complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the Galpha substrate, suggests that unique structural determinants specific to particular RGS protein/Galpha pairings exist and could be used to achieve selective inhibition by small molecules.
G蛋白信号调节（RGS）蛋白可加速Gα亚基的GTP水解，从而促进由G蛋白偶联受体（GPCR）引发的信号传导终止。鉴于RGS蛋白作为GPCR负调节因子的标志性作用，而目前大多数已批准药物都作用于GPCR，因此RGS蛋白有望成为疾病干预靶点。RGS蛋白共享一个标志性的RGS结构域，该结构域在GTP水解的过渡状态下与Gα的相互作用最为强烈；通过结合并稳定Gα的开关区域I和II，RGS结构域的结合从而加速了Gα介导的GTP水解。人类基因组编码了三十多种含有RGS结构域的蛋白质，它们对Gα底物具有不同的特异性。为了便于将它们开发为药物发现靶点，我们采用了系统的结构生物学方法来编目RGS结构域之间存在的结构多样性，并确定它们对Gα选择性差异的分子决定因素。在这里，我们通过核磁共振（NMR）和X射线晶体学确定了RGS蛋白R4、R7、R12和RZ亚家族成员的14种结构，包括10个未复合的RGS结构域和4个RGS结构域/Gα复合物。在RGS结构域的结构架构以及Gα底物的开关III和全螺旋结构域的结合中观察到的异质性表明，特定RGS蛋白/Gα配对存在独特的结构决定因素，可用于实现小分子的选择性抑制。
