{"doi":"10.1101/2021.02.11.430741","title":"An Activator Locks Kv7.1 Channels Open by Electro-Mechanical Uncoupling and Allosterically Modulates its Pore","abstract":"Abstract Loss-of-function mutations in K v 7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with increased risk of arrhythmia and subsequent sudden cardiac death. The discovery of agonistic I Ks modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine ( R )-L3 potently activates K v 7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by ( R )-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we showed that ( R )-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identified novel ( R )-L3-interacting key residues in the lower S4-segment of K v 7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments. Summarizing, we provide structural and functional evidence for two independent K v 7.1 activating mechanisms by a single modulator.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":223185,"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":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":824680,"name":"Julian A. Schreiber","orcid":"0000-0002-3847-7539","position":1,"is_corresponding":false},{"id":825201,"name":"Mark Zaydman","orcid":null,"position":2,"is_corresponding":false},{"id":585537,"name":"Zachary Beller","orcid":"0000-0003-3965-9147","position":3,"is_corresponding":false},{"id":825202,"name":"Sebastian Becker","orcid":null,"position":4,"is_corresponding":false},{"id":825203,"name":"Nadine Ritter","orcid":null,"position":5,"is_corresponding":false},{"id":825204,"name":"Eva Wrobel","orcid":null,"position":6,"is_corresponding":false},{"id":825205,"name":"Nathalie Strutz-Seebohm","orcid":null,"position":7,"is_corresponding":false},{"id":662961,"name":"Niels Decher","orcid":"0000-0002-9433-687X","position":8,"is_corresponding":false},{"id":321395,"name":"Jianmin Cui","orcid":"0000-0002-9198-6332","position":9,"is_corresponding":false},{"id":825206,"name":"Nicole Schmitt","orcid":null,"position":10,"is_corresponding":false},{"id":825207,"name":"Martina Düfer","orcid":null,"position":11,"is_corresponding":false},{"id":825208,"name":"Bernhard Wünsch","orcid":null,"position":12,"is_corresponding":false},{"id":814210,"name":"Guiscard Seebohm","orcid":"0000-0001-9303-5373","position":13,"is_corresponding":false},{"id":825200,"name":"Melina Möller","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-18T23:54:11.061295Z","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":[]}