Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits
Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits
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DOI：
10.1073/pnas.0801508105
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发表时间：
2008-04-29
影响因子：
11.1
通讯作者：
Siderovski, David P.
中科院分区：
文献类型：
--
作者：
Soundararajan, Meera;Willard, Francis S.;Siderovski, David P.
G 蛋白信号传导 (RGS) 蛋白的调节剂可加速 G α 亚基的 GTP 水解，从而促进 G 蛋白偶联受体 (GPCR) 引发的信号传导的终止。 RGS 蛋白作为疾病干预点具有广阔的前景，因为它们作为 GPCR 受体负调节剂的标志性作用，目前大多数已批准药物都针对 GPCR 受体。 RGS 蛋白具有一个标志性的 RGS 结构域，当处于 GTP 水解的过渡状态时，该结构域与 G α 相互作用最频繁；通过结合和稳定 G α 的开关区 I 和 II，RGS 结构域结合会加速 G α 介导的 GTP 水解。人类基因组编码超过三打含有 RGS 结构域的蛋白质，具有不同的 G α 底物特异性。为了促进它们作为药物发现靶标的开发，我们采用了系统的结构生物学方法来对 RGS 结构域之间存在的结构多样性进行编目，并确定其差异 G α 选择性的分子决定因素。在这里，我们确定了来自 RGS 蛋白 R4、R7、R12 和 RZ 亚家族成员的 14 个结构，包括 10 个未复合的 RGS 结构域和 4 个 RGS 结构域/G α 复合物。在 RGS 结构域的结构体系以及开关 III 和 G α 底物的全螺旋结构域的接合中观察到的异质性表明，存在特定于特定 RGS 蛋白/G α 配对的独特结构决定簇，并且可用于实现小分子的选择性抑制。
Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by G alpha 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 G alpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of G alpha, RGS domain binding consequently accelerates G alpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied G alpha 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 G alpha 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/G alpha 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 G alpha substrate, suggests that unique structural determinants specific to particular RGS protein/G alpha pairings exist and could be used to achieve selective inhibition by small molecules.