G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.

中文翻译：

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G蛋白偶联受体的变构和复合。

G蛋白偶联受体（GPCR）代表了最大的细胞表面受体家族。这些受体是天然的变构蛋白，因为通过GPCR激动剂介导的信号传导需要在两个地形不同的结合位点之间传递的受体蛋白发生构象变化，一个是激动剂，另一个是G蛋白。然而，现在越来越被认识到，与激动剂结合的GPCR还可以与其他配体或“辅助”蛋白质形成三元复合物，并且相对于二元激动剂-受体复合物显示出改变的结合和/或信号传导性质。GPCR上的变构位点代表了新的药物靶标，因为相对于经典的正构配体，变构调节剂具有许多理论优势，例如对别构效应的最高水平以及更大的GPCR亚型选择性的潜力。由于变构现象的非竞争性质，对此类效应的检测和定量通常依赖于平衡结合，非平衡动力学和功能性信号传导测定的组合。这篇综述讨论了GPCRs的变构受体模型的发展和特性以及变构作用的检测和定量。此外，我们提供了有关GPCR和可能的内源性变构调节剂上可能的变构位点位置的当前知识的概述。最后，我们讨论了形成GPCR寡聚物或与辅助细胞蛋白复合的GPCR引起的变构作用的可能性。