Dataset Information

Conformational Heterogeneity of Intracellular Loop 3 of the ?-opioid G-protein Coupled Receptor.

ABSTRACT: G-protein coupled receptors (GPCRs), including the ?-opioid receptor, interact with G-proteins and other proteins via their intracellular face as required for signal transduction. However, characterization of the structure of the intracellular face of GPCRs is complicated by the experimental methods used for structural characterization. In the present study we undertook a series of long-time molecular dynamics (MD) simulations, ranging from 1 to 5 ?s, on the ?-opioid receptor in both the dimeric and monomeric states. Results show intracellular loop 2 (ICL2) to sample an equilibrium between coiled and helical states. Intracellular loop 3 (ICL3) samples a wider range of conformations. Previously unobserved ?-sheet structures were primarily sampled in the simulations initiated from the inactive dimer conformation. In contrast, helical structures were sampled in simulations initiated from the active, monomer conformation. Notably, in the dimeric form of the receptor, both intramolecular and intermolecular ?-sheet structures were sampled, with the latter occurring between the two monomers. These results indicate that the sampling of ?-sheet structures can maintain the ICL3 in an inactive conformation that contributes to stabilization of the dimeric form of the receptor via interchain ?-sheet structures.

SUBMITTER: Huang J

PROVIDER: S-EPMC5148698 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Conformational Heterogeneity of Intracellular Loop 3 of the μ-opioid G-protein Coupled Receptor.

Huang Jing J Lakkaraju Sirish Kaushik SK Coop Andrew A MacKerell Alexander D AD

The journal of physical chemistry. B 20161115 46

G-protein coupled receptors (GPCRs), including the μ-opioid receptor, interact with G-proteins and other proteins via their intracellular face as required for signal transduction. However, characterization of the structure of the intracellular face of GPCRs is complicated by the experimental methods used for structural characterization. In the present study we undertook a series of long-time molecular dynamics (MD) simulations, ranging from 1 to 5 μs, on the μ-opioid receptor in both the dimeric ...[more]

PMID: 27801588

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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.

Dataset Information

Conformational Heterogeneity of Intracellular Loop 3 of the ?-opioid G-protein Coupled Receptor.

Publications

Conformational Heterogeneity of Intracellular Loop 3 of the μ-opioid G-protein Coupled Receptor.

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