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

Author

Listed:
  • Libin Ye

    (University of Toronto
    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
    University of Toronto)

  • Nobuyuki Tsuchimura

    (Kwansei Gakuin University)

  • Sacha T. Larda

    (University of Toronto
    University of Toronto)

  • Régis Pomès

    (University of Toronto
    The Hospital for Sick Children)

  • Angel E. García

    (Los Alamos National Laboratory)

  • Oliver P. Ernst

    (University of Toronto
    University of Toronto)

  • Roger K. Sunahara

    (University of California San Diego School of Medicine)

  • R. Scott Prosser

    (University of Toronto
    University of Toronto)

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.

Suggested Citation

  • 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 & R. Scott Prosser, 2018. "Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03314-9
    DOI: 10.1038/s41467-018-03314-9
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    Cited by:

    1. Xudong Wang & Chris Neale & Soo-Kyung Kim & William A. Goddard & Libin Ye, 2023. "Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Dan Kozome & Adnan Sljoka & Paola Laurino, 2024. "Remote loop evolution reveals a complex biological function for chitinase enzymes beyond the active site," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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