Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, 3052 VIC, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, 3052 VIC, Australia.
Cell. 2016 Oct 20;167(3):739-749.e11. doi: 10.1016/j.cell.2016.09.021. Epub 2016 Oct 6.
G protein-coupled receptor (GPCR) signaling, mediated by hetero-trimeric G proteins, can be differentially controlled by agonists. At a molecular level, this is thought to occur principally via stabilization of distinct receptor conformations by individual ligands. These distinct conformations control subsequent recruitment of transducer and effector proteins. Here, we report that ligand efficacy at the calcitonin GPCR (CTR) is also correlated with ligand-dependent alterations to G protein conformation. We observe ligand-dependent differences in the sensitivity of the G protein ternary complex to disruption by GTP, due to conformational differences in the receptor-bound G protein hetero-trimer. This results in divergent agonist-dependent receptor-residency times for the hetero-trimeric G protein and different accumulation rates for downstream second messengers. This study demonstrates that factors influencing efficacy extend beyond receptor conformation(s) and expands understanding of the molecular basis for how G proteins control/influence efficacy. This has important implications for the mechanisms that underlie ligand-mediated biased agonism. VIDEO ABSTRACT.
G 蛋白偶联受体（GPCR）信号转导由异三聚体 G 蛋白介导，可被激动剂差异化调控。从分子水平上看，这主要是通过不同配体稳定受体的不同构象来实现的。这些不同的构象控制随后转导蛋白和效应蛋白的募集。在这里，我们报告降钙素 GPCR（CTR）的配体效能也与配体依赖性 G 蛋白构象改变相关。我们观察到，由于受体结合的异三聚体 G 蛋白的构象差异，G 蛋白三聚复合物对 GTP 破坏的敏感性存在配体依赖性差异。这导致异三聚体 G 蛋白的激动剂依赖性受体停留时间不同，下游第二信使的积累速率也不同。本研究表明，影响效能的因素不仅限于受体构象，还扩展了对 G 蛋白控制/影响效能的分子基础的理解。这对介导偏性激动剂的配体的作用机制具有重要意义。视频摘要。
