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, Raymond C. Stevens
<span title="2014-01-12">2014</span> <i title="Springer Nature America, Inc"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/drfdii35rzaibj3aml5uhvr5xm" style="color: black;">Nature</a> </i> &nbsp;
Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion 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
more &raquo; ... rane 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 Asn131 to alanine or valine augments constitutive arrestin-ergic signaling. Asp95Ala, Asn310Ala, and Asn314Ala mutations transform classical δ-opioid antagonists like naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signaling, revealing that sodium-coordinating residues act as "efficacy-switches" at a prototypic G protein-coupled receptor.
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