Structural insights into μ-opioid receptor activation

By Weijiao Huang, A. Manglik, A. Venkatakrishnan, T. Laeremans, Evan N. Feinberg, Adrian L. Sanborn, Hideaki E. Kato, Kathryn E. Livingston, T. Thorsen, Ralf C. Kling and 8 more. Nature, 2015

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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 muscarinic receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/e409b237b7034bcab33ae4e01b36a76ddedd81ef

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Citations in the corpus

GPCRdb: the G protein‐coupled receptor database – an introduction (2016, neutral): “The receptor families are listed as de ﬁ ned by the nomenclature committee of the International Union of Pharmacology (Southan et al., 2016), whereas gene names are used in order to ﬁ t all receptors. opioid receptor in complex with a nanobody G protein-mimic (Huang et al., 2015).”
DREADDs for Neuroscientists (2016, background): “Additionally, my lab and collaborators have used these structures for the successful structure-guided discovery of novel small molecule modulators (Weiss et al., 2013; Carlsson et al., 2011; Shoichet and Kobilka, 2012; Huang et al., 2015c).”
The Molecular Basis of G Protein–Coupled Receptor Activation (2018, methodology): “49 with ICL2 as well as the end of TM2 is seen in several other active structures (32, 34).”