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Title: Mechanistic insights into allosteric regulation of the A 2A adenosine G protein-coupled receptor by physiological cations

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, Ca 2+ and Mg 2+ 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.
 [1] ; ORCiD logo [2] ;  [3] ;  [4] ;  [1] ;  [3] ;  [1] ; ORCiD logo [5] ;  [2] ; ORCiD logo [6] ; ORCiD logo [4] ;  [1]
  1. Univ. of Toronto, Mississauga, ON (Canada); Univ. of Toronto, Toronto, ON (Canada)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Kwansei Gakuin Univ., Nishinomiya (Japan)
  4. Univ. of California San Diego School of Medicine, La Jolla, CA (United States)
  5. Univ. of Toronto, Toronto, ON (Canada); The Hospital for Sick Children, Toronto, ON (Canada)
  6. Univ. of Toronto, Toronto, ON (Canada)
Publication Date:
Report Number(s):
Journal ID: ISSN 2041-1723
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Nature Publishing Group
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; Biological Science; G protein-coupled receptors; Solution-state NMR
OSTI Identifier: