{"doi":"10.1073/pnas.2409987121","title":"Agonist activation to open the Gα subunit of the GPCR–G protein precoupled complex defines functional agonist activation of TAS2R5","abstract":"G protein-coupled receptors (GPCRs) regulate multiple cellular responses and represent highly successful therapeutic targets. The mechanisms by which agonists activate the G protein are unclear for many GPCR families, including the bitter taste receptors (TAS2Rs). We ascertained TAS2R5 properties by live cell-based functional assays, direct binding affinity measurements using optical resonators, and atomistic molecular dynamics simulations. We focus on three agonists that exhibit a wide range of signal transduction in cells despite comparable ligand–receptor binding energies derived from direct experiment and computation. Metadynamics simulations revealed that the critical barrier to activation is ligand-induced opening of the G protein between the α-helical (AH) and Ras-like domains of Gα subunit from a precoupled TAS2R5-G protein state to the fully activated state. A moderate agonist opens the AH-Ras cleft from 22 Å to 31 Å with an energy gain of −4.8 kcal mol −1 , making GDP water-exposed for signaling. A high-potency agonist had an energy gain of −11.1 kcal mol −1 . The low-potency agonist is also exothermic for Gα opening, but with an energy gain of only −1.4 kcal mol −1 . This demonstrates that TAS2R5 agonist-bound functional potencies are derived from energy gains in the transition from a precoupled complex at the level of Gα opening. Our experimental and computational study provides insights into the activation mechanism of signal transduction that provide a basis for rational design of new drugs.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":443702,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":897011,"name":"Khuong Duy Mac","orcid":"0000-0001-5353-5103","position":1,"is_corresponding":false},{"id":712739,"name":"Hannah R. Strzelinski","orcid":"0000-0002-8461-7061","position":2,"is_corresponding":false},{"id":1258886,"name":"Sandy J. Hoffman","orcid":null,"position":3,"is_corresponding":false},{"id":390872,"name":"Donghwa Kim","orcid":"0000-0002-8994-8513","position":4,"is_corresponding":false},{"id":745959,"name":"Soo-Kyung Kim","orcid":"0000-0002-4498-5441","position":5,"is_corresponding":false},{"id":911543,"name":"Judith Su","orcid":"0000-0002-1005-1755","position":6,"is_corresponding":false},{"id":390875,"name":"Stephen B. Liggett","orcid":"0000-0002-0128-3669","position":7,"is_corresponding":false},{"id":80276,"name":"William A. Goddard","orcid":"0000-0003-0097-5716","position":8,"is_corresponding":false},{"id":897378,"name":"Moon Young Yang","orcid":"0000-0003-4436-8010","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T02:01:29.001453Z","pmid":"39565310","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":[]}