The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor

Hugo Gutiérrez-De-Terán, Arnault Massink, David Rodríguez, Wei Liu, Gye Won Han, Jeremiah S. Joseph, Ilia Katritch, Laura H. Heitman, Lizi Xia, Adriaan P. Ijzerman, Vadim Cherezov, Vsevolod Katritch, Raymond C. Stevens

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

The function of G protein-coupled receptors (GPCRs) can be modulated by a number of endogenous allosteric molecules. In this study, we used molecular dynamics, radioligand binding, and thermostability experiments to elucidate the role of the recently discovered sodium ion binding site in the allosteric modulation of the human A2A adenosine receptor, conserved among class A GPCRs. While the binding of antagonists and sodium ions to the receptor was noncompetitive in nature, the binding of agonists and sodium ions appears to require mutually exclusive conformational states of the receptor. Amiloride analogs can also bind to the sodium binding pocket, showing distinct patterns of agonist and antagonist modulation. These findings suggest that physiological concentrations of sodium ions affect functionally relevant conformational states of GPCRs and can help to design novel synthetic allosteric modulators or bitopic ligands exploiting the sodium ion binding pocket.

Original languageEnglish (US)
Pages (from-to)2175-2185
Number of pages11
JournalStructure
Volume21
Issue number12
DOIs
StatePublished - Dec 3 2013
Externally publishedYes

Fingerprint

G-Protein-Coupled Receptors
Adenosine
Sodium
Binding Sites
Ions
Adenosine A2A Receptors
Amiloride
Molecular Dynamics Simulation
Ligands

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Gutiérrez-De-Terán, H., Massink, A., Rodríguez, D., Liu, W., Han, G. W., Joseph, J. S., ... Stevens, R. C. (2013). The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor. Structure, 21(12), 2175-2185. https://doi.org/10.1016/j.str.2013.09.020

The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor. / Gutiérrez-De-Terán, Hugo; Massink, Arnault; Rodríguez, David; Liu, Wei; Han, Gye Won; Joseph, Jeremiah S.; Katritch, Ilia; Heitman, Laura H.; Xia, Lizi; Ijzerman, Adriaan P.; Cherezov, Vadim; Katritch, Vsevolod; Stevens, Raymond C.

In: Structure, Vol. 21, No. 12, 03.12.2013, p. 2175-2185.

Research output: Contribution to journalArticle

Gutiérrez-De-Terán, H, Massink, A, Rodríguez, D, Liu, W, Han, GW, Joseph, JS, Katritch, I, Heitman, LH, Xia, L, Ijzerman, AP, Cherezov, V, Katritch, V & Stevens, RC 2013, 'The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor', Structure, vol. 21, no. 12, pp. 2175-2185. https://doi.org/10.1016/j.str.2013.09.020
Gutiérrez-De-Terán, Hugo ; Massink, Arnault ; Rodríguez, David ; Liu, Wei ; Han, Gye Won ; Joseph, Jeremiah S. ; Katritch, Ilia ; Heitman, Laura H. ; Xia, Lizi ; Ijzerman, Adriaan P. ; Cherezov, Vadim ; Katritch, Vsevolod ; Stevens, Raymond C. / The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor. In: Structure. 2013 ; Vol. 21, No. 12. pp. 2175-2185.
@article{e08be585855a4eabbe0869e5ed660e55,
title = "The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor",
abstract = "The function of G protein-coupled receptors (GPCRs) can be modulated by a number of endogenous allosteric molecules. In this study, we used molecular dynamics, radioligand binding, and thermostability experiments to elucidate the role of the recently discovered sodium ion binding site in the allosteric modulation of the human A2A adenosine receptor, conserved among class A GPCRs. While the binding of antagonists and sodium ions to the receptor was noncompetitive in nature, the binding of agonists and sodium ions appears to require mutually exclusive conformational states of the receptor. Amiloride analogs can also bind to the sodium binding pocket, showing distinct patterns of agonist and antagonist modulation. These findings suggest that physiological concentrations of sodium ions affect functionally relevant conformational states of GPCRs and can help to design novel synthetic allosteric modulators or bitopic ligands exploiting the sodium ion binding pocket.",
author = "Hugo Guti{\'e}rrez-De-Ter{\'a}n and Arnault Massink and David Rodr{\'i}guez and Wei Liu and Han, {Gye Won} and Joseph, {Jeremiah S.} and Ilia Katritch and Heitman, {Laura H.} and Lizi Xia and Ijzerman, {Adriaan P.} and Vadim Cherezov and Vsevolod Katritch and Stevens, {Raymond C.}",
year = "2013",
month = "12",
day = "3",
doi = "10.1016/j.str.2013.09.020",
language = "English (US)",
volume = "21",
pages = "2175--2185",
journal = "Structure with Folding & design",
issn = "0969-2126",
publisher = "Cell Press",
number = "12",

}

TY - JOUR

T1 - The role of a sodium ion binding site in the allosteric modulation of the A2A adenosine G protein-coupled receptor

AU - Gutiérrez-De-Terán, Hugo

AU - Massink, Arnault

AU - Rodríguez, David

AU - Liu, Wei

AU - Han, Gye Won

AU - Joseph, Jeremiah S.

AU - Katritch, Ilia

AU - Heitman, Laura H.

AU - Xia, Lizi

AU - Ijzerman, Adriaan P.

AU - Cherezov, Vadim

AU - Katritch, Vsevolod

AU - Stevens, Raymond C.

PY - 2013/12/3

Y1 - 2013/12/3

N2 - The function of G protein-coupled receptors (GPCRs) can be modulated by a number of endogenous allosteric molecules. In this study, we used molecular dynamics, radioligand binding, and thermostability experiments to elucidate the role of the recently discovered sodium ion binding site in the allosteric modulation of the human A2A adenosine receptor, conserved among class A GPCRs. While the binding of antagonists and sodium ions to the receptor was noncompetitive in nature, the binding of agonists and sodium ions appears to require mutually exclusive conformational states of the receptor. Amiloride analogs can also bind to the sodium binding pocket, showing distinct patterns of agonist and antagonist modulation. These findings suggest that physiological concentrations of sodium ions affect functionally relevant conformational states of GPCRs and can help to design novel synthetic allosteric modulators or bitopic ligands exploiting the sodium ion binding pocket.

AB - The function of G protein-coupled receptors (GPCRs) can be modulated by a number of endogenous allosteric molecules. In this study, we used molecular dynamics, radioligand binding, and thermostability experiments to elucidate the role of the recently discovered sodium ion binding site in the allosteric modulation of the human A2A adenosine receptor, conserved among class A GPCRs. While the binding of antagonists and sodium ions to the receptor was noncompetitive in nature, the binding of agonists and sodium ions appears to require mutually exclusive conformational states of the receptor. Amiloride analogs can also bind to the sodium binding pocket, showing distinct patterns of agonist and antagonist modulation. These findings suggest that physiological concentrations of sodium ions affect functionally relevant conformational states of GPCRs and can help to design novel synthetic allosteric modulators or bitopic ligands exploiting the sodium ion binding pocket.

UR - http://www.scopus.com/inward/record.url?scp=84889573352&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84889573352&partnerID=8YFLogxK

U2 - 10.1016/j.str.2013.09.020

DO - 10.1016/j.str.2013.09.020

M3 - Article

VL - 21

SP - 2175

EP - 2185

JO - Structure with Folding & design

JF - Structure with Folding & design

SN - 0969-2126

IS - 12

ER -