Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
Biochem Soc Trans. 2013 Feb 1;41(1):154-8. doi: 10.1042/BST20120204.
Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G-protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal α-helices. NMR and crystal structures of the peptide-bound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure-activity series, alanine-replacement mutagenesis and fluorescence analysis to define the molecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets.
B 类 G 蛋白偶联受体（GPCRs）与其他超家族成员共享七次跨膜拓扑结构和 G 蛋白结合，但具有独特的结构和激活方式。这些受体的天然配体是具有 C 端α-螺旋的中等长度肽。与肽结合的二硫键结合受体 N 端结构域的 NMR 和晶体结构表明，这些螺旋占据保守的凹槽；然而，这种相互作用的细节因受体而异。在这篇综述中，我们专注于原型分泌素受体，并使用广泛的内源性光亲和标记、结构-活性系列、丙氨酸取代突变和荧光分析来定义这种相互作用的分子基础。此外，来自计算机分子建模的预测的实验验证为提高结合亲和力提供了基础。这些见解将有助于合理开发作用于这一重要靶标的药物。
