{"doi":"10.17615/qb8y-7n16","title":"Molecular control of δ-opioid receptor signalling","abstract":"Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the 7-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn131 to alanine or valine augments constitutive arrestin-ergic signaling. Asp95Ala, Asn310Ala, and Asn314Ala mutations transform classical δ-opioid antagonists like naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signaling, revealing that sodium-coordinating residues act as “efficacy-switches” at a prototypic G protein-coupled receptor.","journal":"UNC Libraries","year":2020,"id":142441,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":40489,"name":"Vsevolod Katritch","orcid":"0000-0003-3883-4505","position":1,"is_corresponding":false},{"id":225473,"name":"Bryan L. Roth","orcid":"0000-0002-0561-6520","position":2,"is_corresponding":false},{"id":608962,"name":"Gustavo Fenalti","orcid":"0000-0001-6554-2351","position":3,"is_corresponding":false},{"id":103670,"name":"Xi‐Ping Huang","orcid":"0000-0002-2585-653X","position":4,"is_corresponding":false},{"id":266181,"name":"Raymond C. Stevens","orcid":"0000-0002-4522-8725","position":5,"is_corresponding":false},{"id":198890,"name":"Vadim Cherezov","orcid":"0000-0002-5265-3914","position":6,"is_corresponding":false},{"id":608963,"name":"Aaron A. Thompson","orcid":"0000-0003-4314-4242","position":7,"is_corresponding":false},{"id":548260,"name":"Patrick M. Giguère","orcid":"0000-0002-7520-8290","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:17:31.424593Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}