9XF4

Cryo-EM structure of Leu-enkephalin-BMS-986187-bound DOR-Gi2 complex

This is a non-PDB format compatible entry.

Summary for 9XF4

• Entry DOI: 10.2210/pdb9xf4/pdb
• EMDB information: 66801
• Descriptor: Soluble cytochrome b562,Delta-type opioid receptor,Oplophorus-luciferin 2-monooxygenase catalytic subunit, 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, ... (6 entities in total)
• Functional Keywords: complex, pam, agonist, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 5
• Total formula weight: 157447.12

Authors

Zhao, C.,Fu, H.,Tian, X.W.,Cheng, L.,Yan, W.,Shao, Z.H. (deposition date: 2025-10-28, release date: 2026-07-08)

Primary citation

Wang, H.,Miao, Z.,Zhao, C.,Fu, H.,Tian, X.,Liu, X.,Wang, L.,Liu, Y.,Liu, X.,Yong, X.,Su, L.,Yan, W.,Cheng, L.,Chai, R.,Shao, Z.,Ke, B.
Molecular mechanism of allosteric modulation of opioid receptors.
Signal Transduct Target Ther, 11:-, 2026

PubMed Abstract: 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.

PubMed: 42362532
DOI: 10.1038/s41392-026-02759-5

Experimental method

ELECTRON MICROSCOPY (3.05 Å)