{"doi":"10.1101/2022.11.25.517797","title":"The dynamic nature of neurotensin receptor 1 (NTS <sub>1</sub> ) allostery and signaling bias","abstract":"ABSTRACT The neurotensin receptor 1 (NTS 1 ) is a G protein-coupled receptor (GPCR) with promise as a drug target for the treatment of pain, schizophrenia, obesity, addiction, and various cancers. A detailed picture of the NTS 1 structural landscape has been established by X-ray crystallography and cryo-EM and yet, the molecular determinants for why a receptor couples to G protein versus arrestin transducers remain poorly defined. We used 13 C ε H 3 -methionine NMR spectroscopy to show that phosphatidylinositol-4,5-bisphosphate (PIP2) promotes transducer complexation not by dramatically altering the receptor structure but by strengthening long-range allosteric connections, in the form of correlated conformational kinetics, between the orthosteric pocket and highly-conserved activation motifs. β-arrestin-1 further remodels the receptor ensemble by reducing conformational exchange kinetics for a subset of resonances, whereas G protein coupling has little to no effect on the rate. A β-arrestin biased allosteric modulator transforms the NTS 1 :G protein complex into a concatenation of substates, without triggering transducer dissociation, suggesting that it may function by stabilizing signaling incompetent G protein conformations such as the non-canonical state. Together, our work demonstrates the importance of kinetic information to a complete picture of the GPCR activation landscape.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":313336,"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":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255551,"name":"Asuka Inoue","orcid":"0000-0003-0805-4049","position":1,"is_corresponding":false},{"id":996447,"name":"Miquel Pons","orcid":"0000-0002-0586-8322","position":2,"is_corresponding":false},{"id":996448,"name":"Juan Carlos Paniagua","orcid":"0000-0001-7904-2219","position":3,"is_corresponding":false},{"id":996449,"name":"Fei Yan","orcid":"0000-0002-6429-7443","position":4,"is_corresponding":false},{"id":497582,"name":"Hongwei Wu","orcid":"0000-0002-8687-3843","position":5,"is_corresponding":false},{"id":722013,"name":"Scott A. Robson","orcid":"0000-0002-0529-0399","position":6,"is_corresponding":false},{"id":996450,"name":"Ross A. D. Bathgate","orcid":"0000-0001-6301-861X","position":7,"is_corresponding":false},{"id":931698,"name":"Daniel J. Scott","orcid":"0000-0001-6332-2793","position":8,"is_corresponding":false},{"id":303860,"name":"Paul R. Gooley","orcid":"0000-0002-0323-449X","position":9,"is_corresponding":false},{"id":730386,"name":"Joshua J. Ziarek","orcid":"0000-0002-3740-9999","position":10,"is_corresponding":false},{"id":996446,"name":"Fabian Bumbak","orcid":"0000-0003-2739-8197","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T00:33:44.454239Z","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":[]}