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

Autor: Picard LP; Department of Chemical and Physical Sciences, University of Toronto Mississauga (UTM), Mississauga, Ontario, Canada. louisphilippe.picard@utoronto.ca., Orazietti A; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada., Tran DP; School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan., Tucs A; Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.; Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan., Hagimoto S; School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan., Qi Z; Department of Chemical and Physical Sciences, University of Toronto Mississauga (UTM), Mississauga, Ontario, Canada., Huang SK; Department of Chemical and Physical Sciences, University of Toronto Mississauga (UTM), Mississauga, Ontario, Canada., Tsuda K; Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.; Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan., Kitao A; School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan., Sljoka A; Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan. adnan.sljoka@riken.jp.; Department of Chemistry, York University, Toronto, Ontario, Canada. adnan.sljoka@riken.jp., Prosser RS; Department of Chemical and Physical Sciences, University of Toronto Mississauga (UTM), Mississauga, Ontario, Canada. scott.prosser@utoronto.ca.; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. scott.prosser@utoronto.ca.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2024 Jul 31. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1038/s41589-024-01682-6
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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