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FEBS J. 2019 Aug 6. doi: 10.1111/febs.15033. [Epub ahead of print]

A highly conserved δ-opioid receptor region determines RGS4 interaction.

Author information

1
Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
2
Research Programme on Biomedical Informatics (GRIB) - Department of Experimental and Health Sciences, Hospital del Mar Medical Research Institute, Pompeu Fabra University, Barcelona, Spain.
3
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Poland.

Abstract

The δ-opioid receptor (δ-OR) couples to Gi/Go proteins to modulate a variety of responses in the nervous system. Τhe regulator of G protein signalling 4 (RGS4) was previously shown to directly interact within the C-terminal region of δ-OR using its N-terminal domain to negatively modulate opioid receptor signalling. Herein, using molecular dynamics simulations and in vitro pull-down experiments we delimit this interaction to 12 helix 8 residues of δ-ΟR and to the first 17 N-terminal residues (NT) of RGS4. Monitoring the complex arrangement and stabilization between RGS4 and δ-OR by molecular dynamics simulations combined with mutagenesis studies, we defined that two critical interactions are formed: one between Phe329 of helix8 of δ-ΟR and Pro9 of the NT of RGS4 and the other a salt bridge between Glu323 of δ-ΟR and Lys17 of RGS4. Our observations allow drafting for the first time a structural model of a ternary complex including the δ-opioid receptor, a G protein and a RGS protein. Furthermore, the high degree of conservation among opioid receptors of the RGS4-binding region, points to a conserved interaction mode between opioid receptors and this important regulatory protein.

KEYWORDS:

G proteins; RGS4; helix 8; molecular dynamics simulation; opioid receptors

PMID:
31386272
DOI:
10.1111/febs.15033

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