Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072 Australia.
Biochem Pharmacol. 2013 Jan 15;85(2):153-62. doi: 10.1016/j.bcp.2012.09.001. Epub 2012 Sep 11.
Their ubiquitous nature, wide cellular distribution and versatile molecular recognition and signalling help make G-protein binding receptors (GPCRs) the most important class of membrane proteins in clinical medicine, accounting for ∼40% of all current therapeutics. A large percentage of current drugs target the endogenous ligand binding (orthosteric) site, which are structurally and evolutionarily conserved, particularly among members of the same GPCR subfamily. With the recent advances in GPCR X-ray crystallography, new opportunities for developing novel subtype selective drugs have emerged. Given the increasing recognition that the extracellular surface conformation changes in response to ligand binding, it is likely that all GPCRs possess an allosteric site(s) capable of regulating GPCR signalling. Allosteric sites are less structurally conserved than their corresponding orthosteric site and thus provide new opportunities for the development of more selective drugs. Constitutive oligomerisation (dimerisation) identified in many of the GPCRs investigated, adds another dimension to the structural and functional complexity of GPCRs. In this review, we compare 60 crystal structures of nine GPCR subtypes (rhodopsin, ß₂-AR, ß₁-AR, A(2a)-AR, CXCR4, D₃R, H₁R, M₂R, M₃R) across four subfamilies of Class A GPCRs, and discuss mechanisms involved in receptor activation and potential allosteric binding sites across the highly variable extracellular surface of these GPCRs. This analysis has identified a new extracellular salt bridge (ESB-2) that might be exploited in the design of allosteric modulators.
它们无处不在的特性、广泛的细胞分布以及多功能的分子识别和信号转导能力，使 G 蛋白偶联受体 (GPCR) 成为临床医学中最重要的膜蛋白类别，约占当前所有治疗药物的 40%。目前很大一部分药物的作用靶点是内源性配体结合（正位）位点，这些位点在结构和进化上都具有保守性，尤其是在同一 GPCR 亚家族成员之间。随着 GPCR X 射线晶体学的最新进展，开发新型亚型选择性药物的新机会已经出现。鉴于越来越多的人认识到细胞外表面构象会因配体结合而发生变化，因此所有 GPCR 很可能都具有能够调节 GPCR 信号转导的变构（别构）位点。变构位点的结构保守性不如相应的正位位点，因此为开发更具选择性的药物提供了新的机会。在许多研究过的 GPCR 中发现的组成型寡聚化（二聚化），为 GPCR 的结构和功能复杂性增加了另一个维度。在这篇综述中，我们比较了四个 A 类 GPCR 亚家族中的九个 GPCR 亚型（视紫红质、β₂-AR、β₁-AR、A(2a)-AR、CXCR4、D₃R、H₁R、M₂R、M₃R）的 60 个晶体结构，并讨论了受体激活的机制以及这些 GPCR 高度可变的细胞外表面上可能存在的变构结合位点。该分析确定了一个新的细胞外盐桥 (ESB-2)，可能在变构调节剂的设计中得到利用。
