Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
Nat Commun. 2024 Feb 13;15(1):1334. doi: 10.1038/s41467-024-45680-7.
G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using C methyl methionine and F NMR, we investigate the agonist-bound active state of βAR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from βAR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of βAR for G results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.
G 蛋白偶联受体（GPCRs）与不同的 G 蛋白 α 亚基结合具有不同程度的选择性。GPCR 实现这种选择性的机制尚不清楚。使用 C 甲基甲硫氨酸和 F NMR，我们在溶液中研究了βAR 及其与不同 G 蛋白的三元复合物的激动剂结合的活性状态。我们发现三元复合物中的受体采用非常相似的构象。相比之下，完全激动剂结合的受体活性状态采用不同于先前表征的激活中间产物或三元复合物中的βAR 的构象。评估不同 G 蛋白与激动剂结合的受体的结合动力学，我们发现βAR 对 G 的亲和力增加是由于其与受体的结合更快。因此，我们建议在经典和次要偶联之间存在一个由 G 蛋白结合到激动剂结合的受体活性状态的有利程度差异引起的动力学驱动的选择性门。
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