Woo Anthony Yiu-Ho, Song Ying, Zhu Weizhong, Xiao Rui-Ping
Institute of Molecular Medicine, Centre for Life Sciences, Peking University, Beijing, China.
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
Br J Pharmacol. 2015 Dec;172(23):5477-88. doi: 10.1111/bph.13049. Epub 2015 Feb 27.
Seven-transmembrane receptors, also called GPCRs, represent the largest class of drug targets. Upon ligand binding, a GPCR undergoes conformational rearrangement and thereby changes its interaction with effector proteins including the cognate G-proteins and the multifunctional adaptor proteins, β-arrestins. These proteins, by initiating distinct signal transduction mechanisms, mediate one or several functional responses. Recently, the concept of ligand-directed GPCR signalling, also called functional selectivity or biased agonism, has been proposed to explain the phenomenon that chemically diverse ligands exhibit different efficacies towards the different signalling pathways of a single GPCR, and thereby act as functionally selective or 'biased' ligands. Current concepts support the notion that ligand-specific GPCR conformations are the basis of ligand-directed signalling. Multiple studies using fluorescence spectroscopy, X-ray crystallography, mass spectroscopy, nuclear magnetic resonance spectroscopy, single-molecule force spectroscopy and other techniques have provided the evidence to support this notion. It is anticipated that these techniques will ultimately help elucidate the structural basis of ligand-directed GPCR signalling at a precision meaningful for structure-based drug design and how a specific ligand molecular structure induces a unique receptor conformation leading to biased signalling. In this review, we will summarize recent advances in experimental techniques applied in the study of functionally selective GPCR conformations and breakthrough data obtained in these studies particularly those of the β2-adrenoceptor.
七跨膜受体，也称为G蛋白偶联受体（GPCR），是最大的一类药物靶点。在配体结合后，GPCR会发生构象重排，从而改变其与效应蛋白的相互作用，这些效应蛋白包括同源G蛋白和多功能衔接蛋白β抑制蛋白。这些蛋白通过启动不同的信号转导机制，介导一种或几种功能反应。最近，配体导向的GPCR信号传导概念，也称为功能选择性或偏向激动作用，被提出来解释这样一种现象：化学结构多样的配体对单个GPCR的不同信号通路表现出不同的效力，从而作为功能选择性或“偏向性”配体发挥作用。目前的概念支持这样一种观点，即配体特异性的GPCR构象是配体导向信号传导的基础。多项使用荧光光谱、X射线晶体学、质谱、核磁共振光谱、单分子力谱等技术的研究已经提供了支持这一观点的证据。预计这些技术最终将有助于阐明配体导向的GPCR信号传导的结构基础，其精确程度对于基于结构的药物设计具有重要意义，以及特定的配体分子结构如何诱导独特的受体构象从而导致偏向性信号传导。在这篇综述中，我们将总结在功能选择性GPCR构象研究中应用的实验技术的最新进展，以及在这些研究中获得的突破性数据，特别是β2肾上腺素能受体的相关数据。
