9xdr

Cryo-EM structure of asimadoline-BMS-986187-bound KOR-Gi1 complex

spinqualitylabelsall models 9xdr, resolution 2.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9xdr is a 4 chain structure with sequence from Escherichia coli, Homo sapiens, Oplophorus gracilirostris and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.58Å Ligands: A1D6B, A1E0F Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GNAI1_BOVIN Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (By similarity). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (By similarity). The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis (By similarity). Required for cortical dynein-dynactin complex recruitment during metaphase (By similarity).[UniProtKB:P10824][UniProtKB:P63096] 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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