Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations

Ye, Libin; Neale, Chris Andrew; Sljoka, Adnan; Lyda, Brent; Pichugin, Dmitry; Tsuchimura, Nobuyuki; Larda, Sacha T.; Pomes, Regis; Garcia, Angel E.; Ernst, Oliver P.; Sunahara, Roger K.; Prosser, R. Scott

doi:10.1038/s41467-018-03314-9

Mechanistic insights into allosteric regulation of the A_2A adenosine G protein-coupled receptor by physiological cations

Journal Article · Tue Apr 10 04:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-03314-9· OSTI ID:1435536

Ye, Libin ^[1]; ^[2]; Sljoka, Adnan ^[3]; Lyda, Brent ^[4]; Pichugin, Dmitry ^[1]; Tsuchimura, Nobuyuki ^[3]; Larda, Sacha T. ^[1]; ^[5]; Garcia, Angel E. ^[2]; ^[6]; ^[4]; Prosser, R. Scott ^[1]

Univ. of Toronto, Mississauga, ON (Canada); Univ. of Toronto, Toronto, ON (Canada)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Kwansei Gakuin Univ., Nishinomiya (Japan)
Univ. of California San Diego School of Medicine, La Jolla, CA (United States)
Univ. of Toronto, Toronto, ON (Canada); The Hospital for Sick Children, Toronto, ON (Canada)
Univ. of Toronto, Toronto, ON (Canada)

Cations play key roles in regulating G-protein-coupled receptors (GPCRs), although their mechanisms are poorly understood. Here, ¹⁹F NMR is used to delineate the effects of cations on functional states of the adenosine A_2A GPCR. While Na⁺ reinforces an inactive ensemble and a partial-agonist stabilized state, Ca²⁺ and Mg²⁺ shift the equilibrium toward active states. Positive allosteric effects of divalent cations are more pronounced with agonist and a G-protein-derived peptide. In cell membranes, divalent cations enhance both the affinity and fraction of the high affinity agonist-bound state. Molecular dynamics simulations suggest high concentrations of divalent cations bridge specific extracellular acidic residues, bringing TM5 and TM6 together at the extracellular surface and allosterically driving open the G-protein-binding cleft as shown by rigidity-transmission allostery theory. Lastly, an understanding of cation allostery should enable the design of allosteric agents and enhance our understanding of GPCR regulation in the cellular milieu.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL)

Sponsoring Organization:: LDRD; USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1435536

Report Number(s):: LA-UR-18-20653

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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