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

Libin Ye, Chris Neale, Adnan Sljoka, Brent Lyda, Dmitry Pichugin, Nobuyuki Tsuchimura, Sacha T. Larda, Régis Pomès, Angel E. García, Oliver P. Ernst, Roger K. Sunahara and R. Scott Prosser ()
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Libin Ye: University of Toronto
Chris Neale: Los Alamos National Laboratory
Adnan Sljoka: Kwansei Gakuin University
Brent Lyda: University of California San Diego School of Medicine
Dmitry Pichugin: University of Toronto
Nobuyuki Tsuchimura: Kwansei Gakuin University
Sacha T. Larda: University of Toronto
Régis Pomès: University of Toronto
Angel E. García: Los Alamos National Laboratory
Oliver P. Ernst: University of Toronto
Roger K. Sunahara: University of California San Diego School of Medicine
R. Scott Prosser: University of Toronto

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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 A2A 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. An understanding of cation allostery should enable the design of allosteric agents and enhance our understanding of GPCR regulation in the cellular milieu.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03314-9

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DOI: 10.1038/s41467-018-03314-9

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