9ydq | pdb_00009ydq

Human delta opioid receptor complex with mini-Gi and agonist DADLE and allosteric modulator MIPS3614

spinqualitylabelsall models 9ydq, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9ydq is a 6 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 1.94Å Ligands: A1CVG, DAL, DLE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed Opioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The delta-opioid receptor (deltaOR) represents a promising therapeutic target for developing safer opioid analgesics with reduced adverse effects compared to conventional mu-opioid receptor-targeting drugs. Positive allosteric modulators (PAMs) offer advantages over direct agonists by enhancing endogenous opioid signaling while preserving natural spatiotemporal activation patterns, potentially avoiding tolerance and dependence issues. Here, we present high-resolution cryo-EM structures of deltaOR complexed with the peptide agonist DADLE and the PAM MIPS3614, revealing a novel lipid-facing allosteric binding site formed by transmembrane helices 2, 3, and 4. MIPS3614 stabilizes the active receptor conformation through a critical hydrogen bond with residue N131(3.35) in the conserved sodium binding site, a key regulatory region controlling GPCR activation. Comprehensive mutagenesis, molecular dynamics simulations, and structure-activity relationships validate this proposed mechanism. Structure-guided optimization yielded MIPS3983 with enhanced binding affinity and retained cooperativity. Our findings establish the first molecular framework for deltaOR allosteric modulation and provide a structural foundation for the rational design of safer opioid therapeutics. Structure-guided allosteric modulation of the delta opioid receptor.,Mobbs JI, Nguyen MD, Deo O, Bartuzi D, Venugopal H, Alvi S, Pham V, Barnes N, Christopoulos A, Poole DP, Carbone SE, Jorg M, Capuano B, Carlsson J, Gondin AB, Scammells PJ, Valant C, Thal DM bioRxiv [Preprint]. 2025 Oct 17:2025.10.16.682975. doi: , 10.1101/2025.10.16.682975. PMID:41280124 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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