Structural insights into μ-opioid receptor activation
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Figure: μ-opioid receptor (green) bound to the agonist BU72 (orange)
and a G-protein mimetic antibody fragment (blue) |
Brian Kobilka group (Stanford University)
The groups of Brian Kobilka, Bill Weis and Ron Dror (Stanford University) investigated
the structural basis for μ-opioid receptor (μOR) activation. Opioid receptors in the central
nervous system mediate responses to opioid alkaloids and related pharmaceuticals to produce a wide range
of effects including analgesia, euphoria, sedation, respiratory depression and cough suppression, as well
as gastrointestinal effects. Opioid receptors were classified into four subclasses including μ-OR,
δ-OR, κ-OR and the nociceptin receptor. The μOR is the primary target for the majority of
clinically approved opioid analgesics as well as drugs of abuse. To better understand the activation
mechanism and to facilitate the development of analgesic drugs with fewer side effects, the group determined
the structure of µ-opioid receptor bound to agonist BU72 and stabilized in the active state with a G-protein
mimetic camelid antibody fragment (Nb39). Compared with the inactive state μOR, the 2.1-Å active-state
μOR structure revealed how subtle changes in the ligand binding site are associated with large conformational
changes in the cytoplasmic surface. The active μOR structure also revealed an extensive polar network, which
may explain the inefficient allosteric coupling of the orthosteric pocket and the G-protein-coupling interface
observed in other studies for both the μOR and the β2 adrenergic receptor. The μOR
structure offers important insights into shared and subtype-specific mechanisms for the activation of family
A GPCRs.
Citation: Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL,
Kato HE, Livingston KE, Thorsen TS, Kling R, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI,
Steyaert J, Dror RO, Kobilka BK. (2015) Structural insights into μ-opioid receptor activation.
Nature 524, 315-321.
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