Structure
Volume 21, Issue 12, 3 December 2013, Pages 2175-2185
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Article
The Role of a Sodium Ion Binding Site in the Allosteric Modulation of the A2A Adenosine G Protein-Coupled Receptor

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Highlights

  • A multidisciplinary study explores the role of the sodium binding site on A2AAR

  • The allosteric modulation by sodium ions and amilorides on A2AAR is rationalized

  • Sodium ions selectively bind and stabilize the inactive conformation of the A2AAR

  • The binding of sodium ions and agonists is mutually exclusive

Summary

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.

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Present address: Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden

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These authors contributed equally to this work