Department of Pharmacology, Ankara University Faculty of Medicine, Ankara, Turkey.
Department of Medicine, Duke University Medical Center, Durham NC, USA.
Trends Pharmacol Sci. 2014 Dec;35(12):639-47. doi: 10.1016/j.tips.2014.09.010. Epub 2014 Oct 30.
A G protein-coupled receptor (GPCR) is only biologically active when associated with a transduction protein, but it can also switch function by interacting with different types of transduction proteins. Biased agonism arises when the ligand induces the receptor to engage distinct transduction proteins with different efficacies. We briefly review the concept of ligand efficacy, from the classical empirical idea to the current mechanistic views of allosteric regulation in proteins. A combination of these theoretically distinct ideas and methodologies allows us to distinguish true ligand bias from divergences of signalling caused by the system. We also demonstrate a rigorous mathematical connection between the intrinsic efficacy of classical receptor theory and the energetic effect that makes a ligand capable of stabilizing receptor-transducer association in the ternary complex model. This relationship unifies different definitions of efficacy and provides a rational basis for quantifying biased agonism.
G 蛋白偶联受体（GPCR）只有与转导蛋白结合时才具有生物活性，但它也可以通过与不同类型的转导蛋白相互作用来改变功能。当配体诱导受体与不同效率的不同转导蛋白结合时，就会出现偏激动作用。我们简要回顾了配体效力的概念，从经典的经验性观点到当前蛋白质变构调节的机制观点。这些在理论上有区别的想法和方法的结合，使我们能够区分真正的配体偏向和由系统引起的信号转导差异。我们还在经典受体理论的内在效力和使配体能够稳定三元复合物模型中受体-转导体结合的能量效应之间建立了严格的数学联系。这种关系统一了效力的不同定义，并为量化偏激动作用提供了合理的基础。
