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

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

Journal Article · 10 April 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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1435536

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

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

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 90 works

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Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives Urwyler, Stephan Pharmacological Reviews, Vol. 63, Issue 1 https://doi.org/10.1124/pr.109.002501	journal	January 2011
Structure of an Agonist-Bound Human A2A Adenosine Receptor Xu, F.; Wu, H.; Katritch, V. Science, Vol. 332, Issue 6027 https://doi.org/10.1126/science.1202793	journal	March 2011
Biased Signaling Pathways in 2-Adrenergic Receptor Characterized by 19F-NMR Liu, J. J.; Horst, R.; Katritch, V. Science, Vol. 335, Issue 6072 https://doi.org/10.1126/science.1215802	journal	January 2012
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions Liu, W.; Chun, E.; Thompson, A. A. Science, Vol. 337, Issue 6091 https://doi.org/10.1126/science.1219218	journal	July 2012
Isostatic Block and Hole Frameworks Finbow-Singh, Wendy; Whiteley, Walter SIAM Journal on Discrete Mathematics, Vol. 27, Issue 2 https://doi.org/10.1137/100801044	journal	January 2013
The 2.1 Å Resolution Structure of Cyanopindolol-Bound β1-Adrenoceptor Identifies an Intramembrane Na+ Ion that Stabilises the Ligand-Free Receptor Miller-Gallacher, Jennifer L.; Nehmé, Rony; Warne, Tony PLoS ONE, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pone.0092727	journal	March 2014

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GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures Shimada, Ichio; Ueda, Takumi; Kofuku, Yutaka Nature Reviews Drug Discovery, Vol. 18, Issue 1 https://doi.org/10.1038/nrd.2018.180	journal	November 2018
Conformational plasticity of ligand-bound and ternary GPCR complexes studied by 19F NMR of the β1-adrenergic receptor Frei, J. Niclas; Broadhurst, Richard W.; Bostock, Mark J. Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-14526-3	journal	February 2020
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Title: Mechanistic insights into allosteric regulation of the A_2A adenosine G protein-coupled receptor by physiological cations