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

• Published in: Nature chemical biology
• Main Authors: Picard, Louis-Philippe, Orazietti, Alexander, Tran, Duy Phuoc, Tucs, Andrejs, Hagimoto, Sari, Qi, Zhenzhou, Huang, Shuya Kate, Tsuda, Koji, Kitao, Akio, Sljoka, Adnan, Prosser, R Scott
• Format: Journal Article
• Language: English
• Published: United States 31.07.2024

The adenosine A receptor (A R) engages several G proteins, notably G and its cognate G protein. This coupling promiscuity is facilitated by a dynamic ensemble, revealed by F nuclear magnetic resonance imaging of A R and G protein. Two transmembrane helix 6 (TM6) activation states, formerly associated with partial and full agonism, accommodate the differing volumes of G and G . While nucleotide depletion biases TM7 toward a fully active state in A R-G , A R-G 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 R-G complex, failing to stabilize the helix-8 interface with G , 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.