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Structure of the µ-opioid receptor-Gi protein complex.

ABSTRACT: The ?-opioid receptor (?OR) is a G-protein-coupled receptor (GPCR) and the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by ?OR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Here we present the 3.5?Å resolution cryo-electron microscopy structure of the ?OR bound to the agonist peptide DAMGO and nucleotide-free Gi. DAMGO occupies the morphinan ligand pocket, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity. Comparison of the ?OR-Gi complex to previously determined structures of other GPCRs bound to the stimulatory G protein Gs reveals differences in the position of transmembrane receptor helix 6 and in the interactions between the G protein ?-subunit and the receptor core. Together, these results shed light on the structural features that contribute to the Gi protein-coupling specificity of the µOR.

SUBMITTER: Koehl A

PROVIDER: S-EPMC6317904 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Structure of the µ-opioid receptor-Gi protein complex.

Koehl Antoine A Hu Hongli H Maeda Shoji S Zhang Yan Y Qu Qianhui Q Paggi Joseph M JM Latorraca Naomi R NR Hilger Daniel D Dawson Roger R Matile Hugues H Schertler Gebhard F X GFX Granier Sebastien S Weis William I WI Dror Ron O RO Manglik Aashish A Skiniotis Georgios G Kobilka Brian K BK

Nature 20180613 7711

The μ-opioid receptor (μOR) is a G-protein-coupled receptor (GPCR) and the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by μOR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Here we present the 3.5 Å resolution cryo-electron microscopy structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free Gi. DAMGO occupies the morphinan ligand pocket, wit ...[more]

PMID: 29899455

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Project description:ObjectiveThe iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of ?-opioid receptor (MOR)-related G proteins by iboga alkaloids.MethodsIbogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(?-thio)-triphosphate ([(35)S]GTP?S) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.Results and significanceIn rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTP?S binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTP?S binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTP?S binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

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Structure of the µ-opioid receptor-Gi protein complex.

Publications

Structure of the µ-opioid receptor-G<sub>i</sub> protein complex.

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