{"doi":"10.1002/prot.26228","title":"Mapping co‐regulatory interactions among ligand‐binding sites in ryanodine receptor 1","abstract":"Abstract Ryanodine receptor 1 (RyR1) is an intracellular calcium ion (Ca 2+ ) release channel required for skeletal muscle contraction. Although cryo‐electron microscopy identified binding sites of three coactivators Ca 2+ , ATP, and caffeine (CFF), the mechanism of co‐regulation and synergy of these activators is unknown. Here, we report allosteric connections among the three ligand‐binding sites and pore region in (i) Ca 2+ bound‐closed, (ii) ATP/CFF bound‐closed, (iii) Ca 2+ /ATP/CFF bound‐closed, and (iv) Ca 2+ /ATP/CFF bound‐open RyR1 states. We identified two dominant networks of interactions that mediate communication between the Ca 2+ ‐binding site and pore region in Ca 2+ bound‐closed state, which partially overlapped with the pore communications in ATP/CFF bound‐closed RyR1 state. In Ca 2+ /ATP/CFF bound‐closed and ‐open RyR1 states, co‐regulatory interactions were analogous to communications in the Ca 2+ bound‐closed and ATP/CFF bound‐closed states. Both ATP‐ and CFF‐binding sites mediate communication between the Ca 2+ ‐binding site and the pore region in Ca 2+ /ATP/CFF bound—open RyR1 structure. We conclude that Ca 2+ , ATP, and CFF propagate their effects to the pore region through a network of overlapping interactions that mediate allosteric control and molecular synergy in channel regulation.","journal":"Proteins Structure Function and Bioinformatics","year":2021,"id":203722,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"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":466069,"name":"Konstantin I. Popov","orcid":"0000-0002-9394-972X","position":1,"is_corresponding":false},{"id":512917,"name":"Gerhard Meissner","orcid":"0000-0001-5185-4389","position":2,"is_corresponding":false},{"id":149320,"name":"Nikolay V. Dokholyan","orcid":"0000-0002-8225-4025","position":3,"is_corresponding":false},{"id":512915,"name":"Venkat R. Chirasani","orcid":"0000-0003-1416-0438","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-18T23:51:18.050175Z","pmid":"34455637","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":[]}