Publication Date:
2014-01-15
Description:
Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 A high-resolution crystal structure of the human delta-opioid receptor (delta-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive delta-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 beta-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical delta-opioid antagonists such as naltrindole into potent beta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931418/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931418/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fenalti, Gustavo -- Giguere, Patrick M -- Katritch, Vsevolod -- Huang, Xi-Ping -- Thompson, Aaron A -- Cherezov, Vadim -- Roth, Bryan L -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):191-6. doi: 10.1038/nature12944. Epub 2014 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2]. ; 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]. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24413399" target="_blank"〉PubMed〈/a〉
Keywords:
Allosteric Regulation/drug effects/genetics
;
Allosteric Site/drug effects/genetics
;
Arrestins/metabolism
;
Asparagine/genetics/metabolism
;
Crystallography, X-Ray
;
Humans
;
Ligands
;
Models, Molecular
;
Mutagenesis, Site-Directed
;
Naltrexone/analogs & derivatives/chemistry/metabolism/pharmacology
;
Narcotic Antagonists/chemistry/metabolism/pharmacology
;
Receptors, Opioid, delta/agonists/antagonists &
;
inhibitors/*chemistry/genetics/*metabolism
;
*Signal Transduction/drug effects
;
Sodium/metabolism/pharmacology
;
Structure-Activity Relationship
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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