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.
N1 - Funding Information:
This work was supported by NIGMS PSI:Biology grant U54 GM094618 (to R.C.S., V.K., and V.C.). H.G.T. acknowledges the Spanish Ministry of Education for the mobility program (JC2011-0387) and financial support from the Spanish National Plan for R+D (SAF2011-30104). L.H.H., A.P.I., and A.M. thank the Dutch Research Council (NWO) for financial support (NWO-TOP #714.011.001 and NWO-Veni #11188).
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.
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U2 - 10.1016/j.str.2013.09.020
DO - 10.1016/j.str.2013.09.020
M3 - Article
C2 - 24210756
AN - SCOPUS:84889573352
SN - 0969-2126
VL - 21
SP - 2175
EP - 2185
JO - Structure
JF - Structure
IS - 12
ER -