9YDR

Human delta opioid receptor complex with mini-Gi and agonist DADLE and allosteric modulator MIPS3983

This is a non-PDB format compatible entry.

Summary for 9YDR

• Entry DOI: 10.2210/pdb9ydr/pdb
• EMDB information: 72827
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (8 entities in total)
• Functional Keywords: gpcr, opioid receptor, ligand binding, allosteric modulation, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 134711.78

Authors

Mobbs, J.I.,Venugopal, H.,Thal, D.M. (deposition date: 2025-09-23, release date: 2025-12-10)

Primary citation

Mobbs, J.I.,Nguyen, M.D.,Deo, O.,Bartuzi, D.,Venugopal, H.,Alvi, S.,Pham, V.,Barnes, N.,Christopoulos, A.,Poole, D.P.,Carbone, S.E.,Jorg, M.,Capuano, B.,Carlsson, J.,Gondin, A.B.,Scammells, P.J.,Valant, C.,Thal, D.M.
Structure-guided allosteric modulation of the delta opioid receptor.
Biorxiv, 2025

PubMed 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 helices 2, 3, and 4. MIPS3614 stabilizes the active receptor conformation through a critical hydrogen bond with residue N131 in the conserved sodium binding site, a key regulatory region controlling GPCR activation. Comprehensive mutagenesis, molecular dynamics simulations, and structure-activity relationships validate this proposed mechanism. Structure-guided optimization yielded MIPS3983 with enhanced binding affinity and retained cooperativity. Our findings establish the first molecular framework for δOR allosteric modulation and provide a structural foundation for the rational design of safer opioid therapeutics.

PubMed: 41280124
DOI: 10.1101/2025.10.16.682975

Experimental method

ELECTRON MICROSCOPY (2.14 Å)