9xf4

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

spinqualitylabelsall models 9xf4, resolution 3.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9xf4 is a 5 chain structure with sequence from Escherichia coli, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.05Å Ligands: A1D6B Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function C562_ECOLX Electron-transport protein of unknown function.OPRD_HUMAN G-protein coupled receptor that functions as a receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine. Publication Abstract from PubMed 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) mu-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. Molecular mechanism of allosteric modulation of opioid receptors.,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 Signal Transduct Target Ther. 2026 Jun 26;11(1):251. doi: , 10.1038/s41392-026-02759-5. PMID:42362532 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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