Open AccessMolecular control of δ-opioid receptor signalling
Author(s) -
Gustavo Fenalti,
Patrick M. Giguère,
Vsevolod Katritch,
XiPing Huang,
Aaron A. Thompson,
Vadim Cherezov,
Bryan L. Roth,
Raymond C. Stevens
Publication year - 2014
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/nature12944
Subject(s) - allosteric regulation , chemistry , naltrindole , allosteric modulator , functional selectivity , opioid receptor , ion channel , sodium channel , signal transduction , opioid , receptor , agonist , biophysics , sodium , biochemistry , biology , organic chemistry
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.