Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins
Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins
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DOI：
10.1111/j.1747-0285.2006.00373.x
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发表时间：
2006-04-01
影响因子：
3
通讯作者：
Neubig, RR
中科院分区：
文献类型：
--
作者：
Roof, RA;Jin, YF;Neubig, RR
G蛋白信号传导调节因子（Regulators of G-protein signaling，RGS）通过G α亚基加速鸟嘌呤三磷酸水解，并通过G蛋白偶联受体显著抑制信号传导。RGS蛋白的独特表达模式和病理生理调节表明抑制剂可能具有治疗潜力。我们先前报道了基于G α i开关1区域的结构设计RGS 4的约束肽抑制剂（1：Ac-Val-Lys-[Cys-Thr-Gly-Ile-Cys]-Glu-NH 2，S-S），但其作用机制尚未确定。在本研究中，我们表明，1抑制RGS 4通过模仿和竞争与开关1区域的G α 1的结合，肽1显示RGS 4和RGS 8相对于RGS 7的选择性。与1相关的类似物的结构-活性关系被描述为说明RGS抑制的关键特征。最后，我们证明活性的亚甲基二硫醚桥接肽抑制剂，2，调节毒蕈碱受体调节的心房肌细胞钾电流。这些数据支持肽RGS抑制剂的作用机制，证明了它们在天然细胞中的作用，并为RGS抑制剂药物的设计提供了起点。
Regulators of G-protein signaling (RGS) accelerate guanine triphosphate hydrolysis by G alpha-subunits and profoundly inhibit signaling by G protein-coupled receptors. The distinct expression patterns and pathophysiologic regulation of RGS proteins suggest that inhibitors may have therapeutic potential. We previously reported the design of a constrained peptide inhibitor of RGS4 (1: Ac-Val-Lys-[Cys-Thr-Gly-Ile-Cys]-Glu-NH2, S-S) based on the structure of the G alpha i switch 1 region but its mechanism of action was not established. In the present study, we show that 1 inhibits RGS4 by mimicking and competing for binding with the switch 1 region of G alpha i and that peptide 1 shows selectivity for RGS4 and RGS8 versus RGS7. Structure-activity relationships of analogs related to 1 are described that illustrate key features for RGS inhibition. Finally, we demonstrate activity of the methylene dithioether-bridged peptide inhibitor, 2, to modulate muscarinic receptor-regulated potassium currents in atrial myocytes. These data support the proposed mechanism of action of peptide RGS inhibitors, demonstrate their action in native cells, and provide a starting point for the design of RGS inhibitor drugs.