期刊
NATURE
卷 506, 期 7487, 页码 191-196出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12944
关键词
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资金
- National Institutes of Health [P50 GM073197, U54 GM094618, R01 DA017204]
- NIMH Psychoactive Drug Screening Program
- Michael Hooker Chair for Protein Therapeutics and Translational Proteomics
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 angstrom 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.
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