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==Human delta opioid receptor complex with mini-Gi and agonist DADLE and allosteric modulator MIPS3983==
<StructureSection load='9ydr' size='340' side='right'caption='[[9ydr]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ydr]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9YDR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9YDR FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.14&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1CU8:ethyl+3-[(9R,10S)-9-{4-[(2-cyclopropylphenyl)methoxy]phenyl}-6,6-dimethyl-8-oxo-5,7,8,9-tetrahydrotetrazolo[5,1-b]quinazolin-4(6H)-yl]propanoate'>A1CU8</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DLE:D-LEUCINE'>DLE</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9ydr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ydr OCA], [https://pdbe.org/9ydr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ydr RCSB], [https://www.ebi.ac.uk/pdbsum/9ydr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ydr ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/GBB1_HUMAN 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.<ref>PMID:18611381</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:41280124</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ydr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Mobbs JI]]
[[Category: Thal DM]]
[[Category: Venugopal H]]