Molecular control of δ-opioid receptor signalling

Gustavo Fenalti, Patrick M. Giguere, Vsevolod Katritch, Xi-Ping Huang, Aaron A. Thompson, Vadim Cherezov, Bryan L. Roth () and Raymond C. Stevens ()
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Gustavo Fenalti: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Patrick M. Giguere: University of North Carolina Chapel Hill Medical School
Vsevolod Katritch: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Xi-Ping Huang: University of North Carolina Chapel Hill Medical School
Aaron A. Thompson: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Vadim Cherezov: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Bryan L. Roth: University of North Carolina Chapel Hill Medical School
Raymond C. Stevens: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Nature, 2014, vol. 506, issue 7487, 191-196

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature12944

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