The β₂-adrenergic receptor (β₂AR) 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 β₂AR 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 β₂AR-G_s complex revealed the interaction interface of β₂AR-G_s and structural changes upon complex formation [S. G. Rasmussen et al., Nature 477, 549-555 (2011)], yet, the dynamic process of the β₂AR 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 β₂AR 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 β₂AR are qualitatively the same for G_s and G_i1, we detected distinct differences between the β₂AR-G_s and the β₂AR-G_i1 complex in intracellular loop 2 (ICL2). Interactions with ICL2 are essential for activation of G_s These differences between the β₂AR-G_s and β₂AR-G_i1 complexes in ICL2 may be key determinants for G protein coupling selectivity.

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