期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：37
页码：23096-23105
DOI：10.1073/pnas.2009786117
出版社：The National Academy of Sciences of the United States of America
摘要：The β 2 -adrenergic receptor (β 2 AR) is a prototypical G protein-coupled receptor (GPCR) that preferentially couples to the stimulatory G protein G s and stimulates cAMP formation. Functional studies have shown that the β 2 AR also couples to inhibitory G protein G i , activation of which inhibits cAMP formation [R. P. Xiao, Sci. STKE 2001 , re15 (2001)]. A crystal structure of the β 2 AR-G s complex revealed the interaction interface of β 2 AR-G s and structural changes upon complex formation [S. G. Rasmussen et al., Nature 477, 549–555 (2011)], yet, the dynamic process of the β 2 AR signaling through G s and its preferential coupling to G s over G i is still not fully understood. Here, we utilize solution nuclear magnetic resonance (NMR) spectroscopy and supporting molecular dynamics (MD) simulations to monitor the conformational changes in the G protein coupling interface of the β 2 AR in response to the full agonist BI-167107 and G s and G i1 . These results show that BI-167107 stabilizes conformational changes in four transmembrane segments (TM4, TM5, TM6, and TM7) prior to coupling to a G protein, and that the agonist-bound receptor conformation is different from the G protein coupled state. While most of the conformational changes observed in the β 2 AR are qualitatively the same for G s and G i1 , we detected distinct differences between the β 2 AR-G s and the β 2 AR-G i1 complex in intracellular loop 2 (ICL2). Interactions with ICL2 are essential for activation of G s . These differences between the β 2 AR-G s and β 2 AR-G i1 complexes in ICL2 may be key determinants for G protein coupling selectivity.
关键词：GPCR ; β 2 -adrenergic receptor ; NMR spectroscopy ; G protein coupling specificity
