{"doi":"10.1101/2024.12.22.629966","title":"A single main-chain hydrogen bond required to keep GABA <sub>A</sub> receptors closed","abstract":"Abstract GABA A receptors are the primary inhibitory neurotransmitter receptors throughout the central nervous system. Despite significant progress understanding their three-dimensional structure, a critical gap remains in determining the molecular basis for channel gating. We recently identified M2-M3 linker mutations that suggest linker flexibility has asymmetric subunit-specific correlations with channel opening. Here we use non-canonical amino acids (ncAAs) to investigate the role of main-chain H-hydrogen bonds (H-bonds) that may stabilize the M2-M3 linkers. We show that a single main-chain H-bond within the β2 subunit M2-M3 linker inhibits pore opening and is required to keep the unliganded channel closed. Furthermore, breaking this H-bond during channel opening accounts for approximately one third of the activation energy derived from GABA binding. In contrast, the analogous H-bond in the α1 subunit has no effect on gating. Our observations suggest that channel opening involves state-dependent breakage/disruption of a specific main-chain H-bond within the β2 subunit M2-M3 linker.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":508016,"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":0.9522,"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":499489,"name":"Jason D. Galpin","orcid":"0000-0003-1923-5312","position":1,"is_corresponding":false},{"id":1360104,"name":"Samuel Eriksson Lidbrink","orcid":null,"position":2,"is_corresponding":false},{"id":230419,"name":"Yuxuan Zhuang","orcid":"0000-0003-4390-8556","position":3,"is_corresponding":false},{"id":1360105,"name":"Netrang G Desai","orcid":null,"position":4,"is_corresponding":false},{"id":230420,"name":"Rebecca J. Howard","orcid":"0000-0003-2049-3378","position":5,"is_corresponding":false},{"id":43371,"name":"Erik Lindahl","orcid":"0000-0002-2734-2794","position":6,"is_corresponding":false},{"id":459188,"name":"Christopher A. Ahern","orcid":"0000-0002-7975-2744","position":7,"is_corresponding":false},{"id":1012466,"name":"Marcel P Goldschen-Ohm","orcid":"0000-0003-1466-9808","position":8,"is_corresponding":false},{"id":380652,"name":"Cecilia M. Borghese","orcid":"0000-0002-1028-8277","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:11:06.395600Z","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":[]}