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Signal transmission and regulation of G-protein-coupled receptors (GPCRs) by extra- and intracellular ligands occurs via modulation of complex conformational equilibria, but their exact kinetic details and underlying atomic mechanisms are unknown. Here we quantified these dynamic equilibria in the β 1 -adrenergic receptor in its apo form and seven ligand complexes using  1 H/ 15 N NMR spectroscopy. We observe three major exchanging conformations: an inactive conformation ( C  i ), a preactive conformation ( C  p ) and an active conformation ( C  a ), which becomes fully populated in a ternary complex with a G protein mimicking nanobody. The  C  i  ↔  C  p  exchange occurs on the microsecond scale, the  C  p  ↔  C  a  exchange is slower than ~5 ms and only occurs in the presence of two highly conserved tyrosines (Y 5.58 , Y 7.53 ), which stabilize the active conformation of TM6. The  C  p → C  a  chemical shift changes indicate a pivoting motion of the entire TM6 that couples the effector site to the orthosteric ligand pocket.

A high-resolution description of β1-adrenergic receptor functional dynamics and allosteric coupling from backbone NMR