Structure of the δ-opioid receptor bound to naltrindole

By S. Granier, A. Manglik, A. Kruse, T. S. Kobilka, Foon Sun Thian, William I. Weis, Brian K. Kobilka. Nature, 2012

630 citations recorded by the source corpus.

The opioid receptor family comprises three members, the µ-, δ- and κ-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-opioid receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood. The structures of the µ-OR and κ-OR have recently been solved. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the µ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of opioid receptor pharmacology, in which distinct ‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5ca3f515e757fc2de2e717cf591cd7ba4b19da77

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Citations in the corpus

Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor (2013, background): “Significant progress has been made through the development of GPCR fusion proteins, where a T4 lysozyme replaces the conformationally dynamic third intracellular loop (ICL3), for example (Cherezov et al., 2007; Jaakola et al., 2008; Chien et al., 2010; Wu et al., 2010; 2012; Shimamura et al., 2011; ”
Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “These include rhodopsin [124], b2-adrenergic receptor [125], b1-adrenergic receptor [126], adenosine A2A receptor [127], CXCR4 chemokine receptor [128], dopamine D3 receptor [129], histamine H1 receptor [130], sphingosine 1-phosphate S1P1 receptor [131], muscarinic M3 acetylcholine receptor [132], m”
Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance (2013, background): “X-ray crystal structures of the MOR, DOR, and KOR have been recently reported (Granier et al., 2012; Manglik et al., 2012; Wu et al., 2012), as was a structure of the orphanin FQ receptor (Thompson et al., 2012).”
GPCR-I-TASSER: A hybrid approach to G protein-coupled receptor structure modeling and the application to the human genome (2015, methodology): “Illustrative Examples of GPCR Structural Modeling, with Blue and Red Representing Model and Experimental Structure, Respectively (A) Template-based modeling on human opioid (PDB: 4ej4A1) (Granier et al., 2012) and serotonin (PDB: 4iarA1) (Wang et al.”
GPCR Network: a large-scale collaboration on GPCR structure and function (2012, background): “32) , mouse μ-type opioid receptor 33 , mouse δ-type opioid receptor 34 and rat neurotensin receptor 35 .”
Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors (2013, neutral): “…b 1-adrenergic [15], b 2-adrenergic [16], A2A adenosine [17], CXCR4 chemokine [18], dopamine D3 [19], histamine H1 [20], S1P1 sphingosine 1-phosphate [21], M2 muscarinc acetylcholine [22], M3 muscarinic acetylecholine [23], mu-opioid [24], kappa-opioid [25], N/OFQ opioid [26] and delta-opioid [27].”