G-protein-coupled receptors (GPCRs) allow cells to respond to calcium, hormones, and neurotransmitters. Not surprisingly, they currently make up the largest family of validated drug targets. Rational drug design for molecular regulators targeting GPCRs has been limited to theoretical-based computational approaches. X-ray crystallography of intact GPCRs has provided the topological orientation of the seven transmembrane helices, but limited structural information of the extracellular and intracellular loops and protein termini. In this review we detail an NMR-based approach which provides the high-resolution structural features on the extracellular domains of GPCRs and the ligand/receptor complexes formed upon titration of the peptide hormone. The results provide important contact points and a high-resolution description of the ligand/receptor interactions, which may be useful for the rational design of therapeutic agents targeting GPCRs. Recent results from our investigation of the cholecystokinin peptide hormone system are used to highlight this approach.

中文翻译：

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肽激素与G蛋白偶联受体的结合：通过NMR技术的结构表征。

G蛋白偶联受体（GPCR）使细胞对钙，激素和神经递质作出反应。毫不奇怪，它们目前构成经过验证的药物靶标的最大家族。针对靶向GPCR的分子调节剂的合理药物设计仅限于基于理论的计算方法。完整GPCR的X射线晶体学已提供了七个跨膜螺旋的拓扑方向，但有限的细胞外和细胞内环和蛋白质末端的结构信息。在这篇综述中，我们详细介绍了基于NMR的方法，该方法可在GPCR的胞外域和滴定肽激素后形成的配体/受体复合物上提供高分辨率的结构特征。结果提供了重要的接触点和对配体/受体相互作用的高分辨率描述，这可能对合理设计靶向GPCR的治疗药物有用。我们对胆囊收缩素肽激素系统的研究的最新结果被用来强调这种方法。