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Structural insights into µ-opioid receptor activation.

ABSTRACT: Activation of the ?-opioid receptor (?OR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for ?OR activation, here we report a 2.1 Å X-ray crystal structure of the murine ?OR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the ?OR binding pocket are subtle and differ from those observed for agonist-bound structures of the ?2-adrenergic receptor (?2AR) and the M2 muscarinic receptor. Comparison with active ?2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the ?OR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.

SUBMITTER: Huang W

PROVIDER: S-EPMC4639397 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Structural insights into µ-opioid receptor activation.

Huang Weijiao W Manglik Aashish A Venkatakrishnan A J AJ Laeremans Toon T Feinberg Evan N EN Sanborn Adrian L AL Kato Hideaki E HE Livingston Kathryn E KE Thorsen Thor S TS Kling Ralf C RC Granier Sébastien S Gmeiner Peter P Husbands Stephen M SM Traynor John R JR Weis William I WI Steyaert Jan J Dror Ron O RO Kobilka Brian K BK

Nature 20150805 7565

Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic receptor (β2AR) and the M2 muscarini ...[more]

PMID: 26245379

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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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Structural insights into µ-opioid receptor activation.

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Structural insights into µ-opioid receptor activation.

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