Molecular mechanism of allosteric modulation of opioid receptors

作者：Heli 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 · 发表于：Signal Transduction and Targeted Therapy · 年份：2026 · DOI：10.1038/s41392-026-02759-5 · 研究领域：Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology、Pharmacological Receptor Mechanisms and Effects

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 ...