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Structure paper

TitleStructure-guided allosteric modulation of the delta opioid receptor.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateOct 17, 2025
AuthorsJesse I Mobbs / M Deborah Nguyen / Owindeep Deo / Damian Bartuzi / Hariprasad Venugopal / Sadia Alvi / Vi Pham / Nick Barnes / Arthur Christopoulos / Daniel P Poole / Simona E Carbone / Manuela Jörg / Ben Capuano / Jens Carlsson / Arisbel B Gondin / Peter J Scammells / Celine Valant / David M Thal /
PubMed AbstractOpioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The δ-opioid receptor (δOR) ...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.
External linksbioRxiv / PubMed:41280124 / PubMed Central
MethodsEM (single particle)
Resolution1.94 - 2.29 Å
Structure data

72825

9ydp

EMDB-72825, PDB-9ydp:
Human delta opioid receptor complex with mini-Gi and agonist DADLE
Method: EM (single particle) / Resolution: 1.95 Å

72826

9ydq

EMDB-72826, PDB-9ydq:
Human delta opioid receptor complex with mini-Gi and agonist DADLE and allosteric modulator MIPS3614
Method: EM (single particle) / Resolution: 1.94 Å

72827

9ydr

EMDB-72827, PDB-9ydr:
Human delta opioid receptor complex with mini-Gi and agonist DADLE and allosteric modulator MIPS3983
Method: EM (single particle) / Resolution: 2.14 Å

EMDB-72828: receptor focused refinement of human delta opioid receptor complex with mini-Gi and DADLE
Method: EM (single particle) / Resolution: 2.29 Å

EMDB-72829: receptor focused refinement of the human delta opioid complex with mini-Gi, agonist DADLE and allosteric modulator MIPS3614
Method: EM (single particle) / Resolution: 2.22 Å

EMDB-72830: receptor focused refinement of human delta opioid receptor complex with mini-Gi, agonist DADLE and allosteric modulator MIPS3983
Method: EM (single particle) / Resolution: 2.14 Å

EMDB-72831: conensus map of the human delta opioid complex with mini-Gi, agonist DADLE and allosteric modulator BMS-986187
Method: EM (single particle) / Resolution: 1.94 Å

EMDB-72832: receptor focused refinement of human delta opioid complex with mini-Gi, agonist DADLE and allosteric modulator BMS-986187
Method: EM (single particle) / Resolution: 2.12 Å

Chemicals

ChemComp-HOH:
WATER

PDB-1cvg:
Unknown entry

PDB-1cu8:
Unknown entry

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / GPCR / opioid receptor / ligand binding / allosteric modulation

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