Decoding Partner Specificity of Opioid Receptor Family

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.

MUG: A mutation overview of GPCR subfamily A17 receptors

“…Mutations in residues that interact with G protein were found essentially in dopamine (D 1 R, D 2 R, D 3 R, D 4 R, D 5 R) and adrenergic (α 1B -adrenoreceptor, α 2B -adrenoreceptor, and β 1/2/3 -adrenoreceptors) families. Many GPCRs can interact with a different downstream effector, β-arrestin [114] , [115] , [116] . However, there is weak information reported on the possible effects of mutations at the site of interaction of GPCRs with β-Arrestin.…”

The life and times of endogenous opioid peptides: Updated understanding of synthesis, spatiotemporal dynamics, and the clinical impact in alcohol use disorder

“…They also found hits without any C-terminal amidation motif, which are likely not biologically relevant. For EM-1, the 12 hits included SH2 containing proteins, olfactory receptor 51V1, trace amine-associated GPCRs 1–5 and Gα q s, which are effectors of MOR among other GPCRs ( Barreto et al, 2021 ; Minami et al, 2010 ; Psifogeorgou et al, 2011 ). For EM-2, the 20 the hits were more diverse, including Galacto-cerebrosidase, Ataxin 1, choline kinase, Insulin-like growth factor receptor 1 precursor, and secreted frizzled-related protein 5.…”

Class A and C GPCR Dimers in Neurodegenerative Diseases

“…ORs are activated by their endogenous opioid ligands that are released by neurons such as dynorphins, enkephalins, endorphins, endomorphins and nociceptin, but also by exogenous opiate drugs [ 233 - 239 ]. Since the ORs are all coupled to G i proteins, their activation characteristically inhibits neuronal firing as well as neurotransmitter and hormone release [ 233 , 240 - 243 ]. The opioid system plays an important role in hedonic homeostasis, mood and well-being, including a large number of sensory, motivational, emotional and cognitive functions and addictive behaviours [ 233 , 244 ].…”