title: Molecular control of δ-opioid receptor signalling.
abstract: Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive β-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical δ-opioid antagonists such as naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.
authors.affiliation: 1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2].
authors.forename: Gustavo
authors.initials: G
authors.lastname: Fenalti
authors.affiliation: 1] National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA [2].
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Giguere
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Thompson
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program and Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000495:Allosteric Site / Q000187:drug effects / Q000235:genetics; D019390:Arrestins / Q000378:metabolism; D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D008024:Ligands; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D000071557:beta-Arrestins; D009271:Naltrexone; D001216:Asparagine; D012964:Sodium; C055382:naltrindole