The Role of a Sodium Ion Binding Site in the Allosteric Modulation of the A_2A Adenosine G Protein-Coupled Receptor

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• 作者：Hugo Guti茅rrez-de-Ter谩n ; Arnault Massink ; David Rodr铆guez ; Wei Liu ; Gye聽Won Han ; Jeremiah聽S. Joseph ; Ilia Katritch ; Laura聽H. Heitman ; Lizi Xia ; Adriaan聽P. IJzerman ; Vadim Cherezov ; Vsevolod Katritch ; Raymond聽C. Stevens
• 刊名：Structure
• 出版年：3 December, 2013
• 年：2013
• 卷：21
• 期：12
• 页码：2175-2185
• 全文大小：2966 K

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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 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.