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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, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity. Comparison of the μOR-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 α-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.

Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways.sup.1,2. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human [beta]-arrestin 1 ([beta]arr1([DELTA]CT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with [beta]arr1([DELTA]CT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions. A cryo-electron microscopy structure of the neurotensin receptor 1 in complex with [beta]-arrestin 1 is reported., Author(s): Weijiao Huang [sup.1] , Matthieu Masureel [sup.1] , Qianhui Qu [sup.1] [sup.2] , John Janetzko [sup.1] , Asuka Inoue [sup.3] , Hideaki E. Kato [sup.1] [sup.6] , Michael J. [...]

The [mu]-opioid receptor ([mu]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 [mu]OR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein G.sub.i. Here we present the 3.5 Å resolution cryo-electron microscopy structure of the [mu]OR bound to the agonist peptide DAMGO and nucleotide-free G.sub.i. 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 [mu]OR-G.sub.i complex to previously determined structures of other GPCRs bound to the stimulatory G protein G.sub.s reveals differences in the position of transmembrane receptor helix 6 and in the interactions between the G protein [alpha]-subunit and the receptor core. Together, these results shed light on the structural features that contribute to the G.sub.i protein-coupling specificity of the [micro]OR. A cryo-electron structure of the [micro]-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein G.sub.i reveals structural determinants of its G protein-binding specificity., Author(s): Antoine Koehl [sup.1] , Hongli Hu [sup.1] [sup.2] , Shoji Maeda [sup.2] , Yan Zhang [sup.1] [sup.2] , Qianhui Qu [sup.1] [sup.2] , Joseph M. Paggi [sup.1] [sup.2] [sup.3] [...]

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Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein G[sub.s]. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1RG[sub.s] complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the 5-helix of the Ras-like domain of G[sub.s]. These results provide a structural framework for understanding class B GPCR activation through hormone binding., Author(s): Yan Zhang [1]; Bingfa Sun [2]; Dan Feng [2]; Hongli Hu [1]; Matthew Chu [2]; Qianhui Qu [1]; Jeffrey T. Tarrasch [1]; Shane Li [2]; Tong Sun Kobilka [2]; [...]

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, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity. Comparison of the μOR-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 α-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. A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein Gi reveals structural determinants of its G protein-binding specificity. [ABSTRACT FROM AUTHOR]

The neurotrophin receptor p75NTR conveys multiple signals via its intracellular death domain. However, how the death domain is activated and interacts with downstream adaptors remains unclear. Here, we report two crystal structures of the p75NTR death domain in the form of a non-covalent asymmetric dimer and a Cys379-Cys379 disulfide bond linked symmetric dimer, respectively. These two dimer arrangements have not previously been observed in other death domain-containing proteins. Further analysis shows that both the Cys379-Cys379 disulfide linked and non-covalent full-length p75NTR dimers are present on the cell surface. These observations suggest that various oligomers may exist simultaneously on the cell surface, and that p75NTR activation and signalling may be modulated by neurotrophins or other factors via inducing a shift of the equilibrium between different oligomeric states. [ABSTRACT FROM AUTHOR]