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. 2021 Sep 21:8:715215.
doi: 10.3389/fmolb.2021.715215. eCollection 2021.

Decoding Partner Specificity of Opioid Receptor Family

Carlos A V Barreto  1   2 , Salete J Baptista  1   3 , António J Preto  1   2 , Daniel Silvério  1 , Rita Melo  1   4 , Irina S Moreira  4   5
Affiliations

Decoding Partner Specificity of Opioid Receptor Family

Carlos A V Barreto et al. Front Mol Biosci. .

Abstract

This paper describes an exciting big data analysis compiled in a freely available database, which can be applied to characterize the coupling of different G-Protein coupled receptors (GPCRs) families with their intracellular partners. Opioid receptor (OR) family was used as case study in order to gain further insights into the physiological properties of these important drug targets, known to be associated with the opioid crisis, a huge socio-economic issue directly related to drug abuse. An extensive characterization of all members of the ORs family (μ (MOR), δ (DOR), κ (KOR), nociceptin (NOP)) and their corresponding binding partners (ARRs: Arr2, Arr3; G-protein: Gi1, Gi2, Gi3, Go, Gob, Gz, Gq, G11, G14, G15, G12, Gssh, Gslo) was carried out. A multi-step approach including models' construction (multiple sequence alignment, homology modeling), complex assembling (protein complex refinement with HADDOCK and complex equilibration), and protein-protein interface characterization (including both structural and dynamics analysis) were performed. Our database can be easily applied to several GPCR sub-families, to determine the key structural and dynamical determinants involved in GPCR coupling selectivity.

Keywords: G-protein; GPCRs; arrestin; database; functional signature; opioid receptor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Representation of the OR pipeline.
FIGURE 2
FIGURE 2
Key interactions between OR and G-Proteins. Only common interactions between the four receptors were depicted. The Ballesteros-Weinstein (BW) numbering scheme, which allows the comparison of any amino acid residue in the structurally conserved TM helices of GPCRs, was used. For ICL2, residues were labeled 34. X, indicating the positions between TM3 and TM4. X.50 was once again attributed to the most conserved residue. DOR residues numbers were used for ICL3 numbering, since this substructure is not conserved among OR.
FIGURE 3
FIGURE 3
Common interaction binding motifs in the OR family. Receptors and partners are both represented as surface. 3D structures correspond to DOR-Gi1, KOR-Gssh, DOR-Gq and KOR-G12 (from top to bottom). Residues reported in Figure 2 were colored by their subdomain using the color scheme available at the sequence alignment on the webserver. Receptor: TM2 - yellow; TM3 - light green; ICL2 - dark green, TM4 - lime; TM5 - light blue; ICL3 - dark blue; TM6 - blue, TM7 - purple; H8 - red. Partner: HN - light green, hns1 - dark teal; S3 - yellow; h4s6 - light blue; H5 - dark grey.
See this image and copyright information in PMC

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