Balancing G protein selectivity and efficacy in the adenosine A 2A receptor.

The adenosine A 2A receptor (A 2A R) engages several G proteins, notably G o and its cognate G s protein. This coupling promiscuity is facilitated by a dynamic ensemble, revealed by 19 F nuclear magnetic resonance imaging of A 2A R and G protein. Two transmembrane helix 6 (TM6) activation states, formerly associated with partial and full agonism, accommodate the differing volumes of G s and G o . While nucleotide depletion biases TM7 toward a fully active state in A 2A R-G s , A 2A R-G o is characterized by a dynamic inactive/intermediate fraction. Molecular dynamics simulations reveal that the NPxxY motif, a highly conserved switch, establishes a unique configuration in the A 2A R-G o complex, failing to stabilize the helix-8 interface with G s , and adoption of the active state. The resulting TM7 dynamics hamper G protein coupling, suggesting kinetic gating may be responsible for reduced efficacy in the noncognate G protein complex. Thus, dual TM6 activation states enable greater diversity of coupling partners while TM7 dynamics dictate coupling efficacy.