{"doi":"10.1085/jgp.202313503","title":"Mechanisms of a novel regulatory light chain–dependent cardiac myosin inhibitor","abstract":"Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening of the left ventricle (LV), hypercontractility, and impaired relaxation. HCM is caused primarily by heritable mutations in sarcomeric proteins, such as β myosin heavy chain. Until recently, medications in clinical use for HCM did not directly target the underlying contractile changes in the sarcomere. Here, we investigate a novel small molecule, RLC-1, identified in a bovine cardiac myofibril high-throughput screen. RLC-1 is highly dependent on the presence of a regulatory light chain to bind to cardiac myosin and modulate its ATPase activity. In demembranated rat LV trabeculae, RLC-1 decreased maximal Ca2+-activated force and Ca2+ sensitivity of force, while it increased the submaximal rate constant for tension redevelopment. In myofibrils isolated from rat LV, both maximal and submaximal Ca2+-activated force are reduced by nearly 50%. Additionally, the fast and slow phases of relaxation were approximately twice as fast as DMSO controls, and the duration of the slow phase was shorter. Structurally, x-ray diffraction studies showed that RLC-1 moved myosin heads away from the thick filament backbone and decreased the order of myosin heads, which is different from other myosin inhibitors. In intact trabeculae and isolated cardiomyocytes, RLC-1 treatment resulted in decreased peak twitch magnitude and faster activation and relaxation kinetics. In conclusion, RLC-1 accelerated kinetics and decreased force production in the demembranated tissue, intact tissue, and intact whole cells, resulting in a smaller cardiac twitch, which could improve the underlying contractile changes associated with HCM.","journal":"The Journal of General Physiology","year":2024,"id":468724,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"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":162438,"name":"Qing-Fen Gan","orcid":null,"position":1,"is_corresponding":false},{"id":275489,"name":"Ming Yu","orcid":"0000-0002-8812-976X","position":2,"is_corresponding":false},{"id":665144,"name":"Na Sa","orcid":"0000-0001-8599-4371","position":3,"is_corresponding":false},{"id":1031799,"name":"Saffie Mohran","orcid":"0000-0003-0728-9882","position":4,"is_corresponding":false},{"id":1301778,"name":"Yuanhua Cheng","orcid":"0000-0003-4093-5006","position":5,"is_corresponding":false},{"id":476803,"name":"Galina Flint","orcid":"0000-0003-3993-5156","position":6,"is_corresponding":false},{"id":1253598,"name":"Stephanie Neys","orcid":"0009-0007-3455-9370","position":7,"is_corresponding":false},{"id":1031800,"name":"Chengqian Gao","orcid":"0009-0000-5107-5326","position":8,"is_corresponding":false},{"id":1059400,"name":"Devin Nissen","orcid":"0000-0001-9751-0901","position":9,"is_corresponding":false},{"id":400434,"name":"Timothy S. McMillen","orcid":"0000-0001-5261-3229","position":10,"is_corresponding":false},{"id":443186,"name":"Anthony Asencio","orcid":"0000-0002-8147-0180","position":11,"is_corresponding":false},{"id":355530,"name":"Weikang Ma","orcid":"0000-0001-9535-7114","position":12,"is_corresponding":false},{"id":355536,"name":"Thomas C. Irving","orcid":"0000-0003-4848-3323","position":13,"is_corresponding":false},{"id":472057,"name":"Farid Moussavi‐Harami","orcid":"0000-0002-0189-7214","position":14,"is_corresponding":false},{"id":347667,"name":"Michael Regnier","orcid":"0000-0001-5437-9851","position":15,"is_corresponding":false},{"id":476801,"name":"Kristina B. Kooiker","orcid":"0000-0003-1817-9080","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:05:23.500722Z","pmid":"39083045","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":[]}