Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada; Department of Physiology and Pharmacology, Karolinska Institutet, S17177, Stockholm, Sweden.
Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Curr Opin Struct Biol. 2021 Aug;69:142-149. doi: 10.1016/j.sbi.2021.04.006. Epub 2021 May 26.
It should come as no surprise that G protein-coupled receptors (GPCRs) continue to occupy the focus of drug discovery efforts. Their widespread expression and broad role in signal transduction underline their importance in human physiology. Despite more than 800 GPCRs sharing a common architecture, unique differences govern ligand specificity and pathway selectivity. From the relatively simplified view offered by classical radioligand binding assays and contractility responses in organ baths, the road from ligand binding to biological action has become more and more complex as we learn about the molecular mediators that underly GPCR activation and translate it to physiological outcomes. In particular, the development of biosensors has evolved over the years to dissect the capacity of a given receptor to activate individual pathways. Here, we discuss how recent biosensor development has reinforced the idea that biased signaling may become mainstream in drug discovery programs.
毫不奇怪，G 蛋白偶联受体（GPCRs）仍然是药物发现努力的焦点。它们广泛的表达和在信号转导中的广泛作用突出了它们在人类生理学中的重要性。尽管有 800 多种 GPCR 具有共同的结构，但独特的差异决定了配体的特异性和途径的选择性。从经典放射性配体结合测定和器官浴中的收缩反应提供的相对简化的观点来看，随着我们了解构成 GPCR 激活并将其转化为生理结果的分子介质，从配体结合到生物作用的过程变得越来越复杂。特别是，生物传感器的发展多年来一直在发展，以剖析给定受体激活单个途径的能力。在这里，我们讨论了最近的生物传感器发展如何加强了这样一种观点，即偏向信号传递可能成为药物发现计划中的主流。
