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Propagation of the Allosteric Modulation Induced by Sodium in the δ-Opioid Receptor. | LitMetric

Propagation of the Allosteric Modulation Induced by Sodium in the δ-Opioid Receptor.

Chemistry

Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, 106 91, Stockholm, Sweden.

Published: April 2017

AI Article Synopsis

Article Abstract

Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the δ-opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp274 to propagate the modulation to helices 5 and 6, which further transmits along the helices and regulates their positions on the intracellular side. This mechanism is supported by subsequent functional assays. Remarkably, our results highlight the contrast between the allosteric effects towards two GPCR partners, the G protein and β-arrestin, as indicated by the fact that the allosteric modulation initiated by the sodium ion significantly affects the β-arrestin recruitment, while it alters the G protein signaling only moderately. We believe that the mechanism revealed in this work can be used to explain allosteric effects initiated by sodium in other GPCRs since the allosteric sodium is highly conserved across GPCRs.

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Source
http://dx.doi.org/10.1002/chem.201605575DOI Listing

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