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Structure paper

TitleMolecular mechanism of allosteric modulation of opioid receptors.
Journal, issue, pagesSignal Transduct Target Ther, Vol. 11, Year 2026
Publish dateOct 29, 2025
AuthorsHeli Wang / Zhuang Miao / Chang Zhao / Hong Fu / Xiaowen Tian / Xinlei Liu / Lei Wang / Yuan Liu / Xingyu Liu / Xihao Yong / Lantian Su / Wei Yan / Lin Cheng / Renjie Chai / Zhenhua Shao / Bowen Ke /
PubMed AbstractOpioid analgesics provide potent pain relief but are limited by severe adverse effects, tolerance, and interindividual genetic variability in response. Poly-pharmacology and allosteric modulation of ...Opioid analgesics provide potent pain relief but are limited by severe adverse effects, tolerance, and interindividual genetic variability in response. Poly-pharmacology and allosteric modulation of opioid receptors offer promising strategies to enhance analgesic efficacy while mitigating these limitations. Pan-positive allosteric modulators (pan-PAMs), which simultaneously potentiate multiple opioid receptor subtypes, integrate the advantages of both approaches and represent an emerging therapeutic paradigm for pain management. However, the molecular mechanisms underlying pan-PAM activity at opioid receptors remain poorly understood. Here, we characterize BMS-986187 as a pan-PAM of opioid receptors and report the cryo-electron microscopy (cryo-EM) structures of multiple opioid receptor subtypes bound to this modulator, revealing a previously unidentified allosteric pocket. Structural and functional analyses revealed a conserved binding motif that mediates PAM recognition across the opioid receptor family and revealed the essential contributions of key opioid receptor residues to allosteric modulation by BMS-986187. Functionally, BMS-986187 enhances analgesic efficacy through an opioid-sparing effect, allowing lower opioid doses and reducing side effects, while restoring activity in loss-of-function (LOF) μ-opioid receptor variants. These findings define a previously unrecognized allosteric site in opioid receptors and establish a structural framework for the rational design of safer and more effective opioid therapeutics through allosteric modulation.
External linksSignal Transduct Target Ther / PubMed:42362532 / PubMed Central
MethodsEM (single particle)
Resolution2.52 - 3.22 Å
Structure data

66723
EMDB Unreleased entry

9xc6

EMDB-66723, PDB-9xc6:
Cryo-EM structure of BMS-986187-bound MOR-Gi1 complex
Method: EM (single particle) / Resolution: 3.04 Å


EMDB Unreleased entry

EMDB-66725: BMS-986187-bound MOR-Gi1 G Protein EM map
Method: EM (single particle) / Resolution: 3.04 Å


EMDB Unreleased entry

EMDB-66726: The overall map of BMS-986187-bound MOR-Gi1 complex
Method: EM (single particle) / Resolution: 3.04 Å


EMDB Unreleased entry

EMDB-66730: The receptor local map of BMS-986187-bound MOR-Gi1 complex
Method: EM (single particle) / Resolution: 3.04 Å

66771
EMDB Unreleased entry

9xdq

EMDB-66771, PDB-9xdq:
Cryo-EM structure of BMS986187 bound DOR-Gi complex
Method: EM (single particle) / Resolution: 2.79 Å

66773
EMDB Unreleased entry

9xdr

EMDB-66773, PDB-9xdr:
Cryo-EM structure of asimadoline-BMS-986187-bound KOR-Gi1 complex
Method: EM (single particle) / Resolution: 2.58 Å

66801
EMDB Unreleased entry

9xf4

EMDB-66801, PDB-9xf4:
Cryo-EM structure of Leu-enkephalin-BMS-986187-bound DOR-Gi2 complex
Method: EM (single particle) / Resolution: 3.05 Å


EMDB Unreleased entry

EMDB-66825: The receptor local map of BMS-986187-bound DOR-Gi2 complex
Method: EM (single particle) / Resolution: 2.95 Å


EMDB Unreleased entry

EMDB-66826: The G PROTEIN map of BMS-986187-bound DOR-Gi1 complex
Method: EM (single particle) / Resolution: 2.66 Å


EMDB Unreleased entry

EMDB-66827: The overall map of BMS-986187-bound DOR-Gi2 complex
Method: EM (single particle) / Resolution: 2.79 Å


EMDB Unreleased entry

EMDB-66828: The receptor local map of asimadoline-BMS-986187-bound KOR-Gi1 complex
Method: EM (single particle) / Resolution: 2.73 Å


EMDB Unreleased entry

EMDB-66829: The G PROTEIN map of asimadoline-BMS-986187-bound KOR-Gi1 complex
Method: EM (single particle) / Resolution: 2.52 Å


EMDB Unreleased entry

EMDB-66830: The overall map of asimadoline-BMS-986187-bound KOR-Gi1 complex
Method: EM (single particle) / Resolution: 2.58 Å


EMDB Unreleased entry

EMDB-66831: The receptor local map of Leu-enkephalin-BMS-986187-bound DOR-Gi complex
Method: EM (single particle) / Resolution: 3.22 Å


EMDB Unreleased entry

EMDB-66832: The Gi protein local map of Leu-enkephalin-BMS-986187-bound DOR-Gi complex
Method: EM (single particle) / Resolution: 2.87 Å


EMDB Unreleased entry

EMDB-66833: The overall map of Leu-enkephalin-BMS-986187-bound DOR-Gi complex
Method: EM (single particle) / Resolution: 3.05 Å

Chemicals

PDB-1d6b:
SOLUTION STRUCTURE OF DEFENSIN-LIKE PEPTIDE-2 (DLP-2) FROM PLATYPUS VENOM

PDB-1esg:
RESTRICTION ENDONUCLEASE BAMHI BOUND TO A NON-SPECIFIC DNA.

PDB-1e0f:
Crystal structure of the human alpha-thrombin-haemadin complex: an exosite II-binding inhibitor

Source
  • homo sapiens (human)
  • oplophorus gracilirostris (arthropod)
  • synthetic construct (others)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Complex / Agonist / PAM

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