The role of a sodium ion binding site in the allosteric modulation of the A(2A) adenosine G protein-coupled receptor. Structure 2013 Dec 03;21(12):2175-85
Date
11/12/2013Pubmed ID
24210756Pubmed Central ID
PMC3858454DOI
10.1016/j.str.2013.09.020Scopus ID
2-s2.0-84889573352 (requires institutional sign-in at Scopus site) 105 CitationsAbstract
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 A(2A) 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 List
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 RCAuthor
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine A2 Receptor AgonistsAdenosine A2 Receptor Antagonists
Allosteric Regulation
Allosteric Site
Amiloride
Amino Acid Sequence
Cations, Monovalent
HEK293 Cells
Hot Temperature
Humans
Molecular Dynamics Simulation
Molecular Sequence Data
Protein Conformation
Protein Stability
Radioligand Assay
Receptor, Adenosine A2A
Sodium
