What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.
What is biased efficacy? Defining the relationship between intrinsic efficacy and free energy coupling.
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DOI：
10.1016/j.tips.2014.09.010
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发表时间：
2014-12
影响因子：
13.8
通讯作者：
H. Onaran;S. Rajagopal;T. Costa
中科院分区：
文献类型：
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作者：
H. Onaran;S. Rajagopal;T. Costa
G蛋白偶联受体只有在与转导蛋白结合时才具有生物学活性，但它也可以通过与不同类型的转导蛋白相互作用来切换功能。当配体诱导受体以不同的效率参与不同的转导蛋白时，就会产生有偏见的激动剂。我们简要回顾了配基功效的概念，从经典的经验观点到目前蛋白质变构调节的机制观点。这些理论上截然不同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分歧。我们还证明了经典受体理论的内在有效性与能量效应之间的严格数学联系，在三元络合物模型中，能量效应使配体能够稳定受体-转导分子的结合。这种关系统一了对疗效的不同定义，并为量化有偏见的激动症提供了合理的基础。
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.