Structure-guided allosteric modulation of the delta opioid receptor.

ABSTRACT: Opioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The δ-opioid receptor (δOR) represents a promising therapeutic target for developing safer opioid analgesics with reduced adverse effects compared to conventional μ-opioid receptor-targeting drugs. Positive allosteric modulators (PAMs) offer advantages over direct agonists by enhancing endogenous opioid signaling while preserving natural spatiotemporal activation patterns, potentially avoiding tolerance and dependence issues. Here, we present high-resolution cryo-EM structures of δOR complexed with the peptide agonist DADLE and the PAM MIPS3614, revealing a novel lipid-facing allosteric binding site formed by transmembrane

SUBMITTER: Mobbs JI 

PROVIDER: S-EPMC12632917 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature