{"doi":"10.7554/elife.75568","title":"Ca2+ inactivation of the mammalian ryanodine receptor type 1 in a lipidic environment revealed by cryo-EM","abstract":"Activation of the intracellular Ca 2+ channel ryanodine receptor (RyR) triggers a cytosolic Ca 2+ surge, while elevated cytosolic Ca 2+ inhibits the channel in a negative feedback mechanism. Cryogenic electron microscopy of rabbit RyR1 embedded in nanodiscs under partially inactivating Ca 2+ conditions revealed an open and a closed-inactivated conformation. Ca 2+ binding to the high-affinity site engages the central and C-terminal domains into a block, which pries the S6 four-helix bundle open. Further rotation of this block pushes S6 toward the central axis, closing (inactivating) the channel. Main characteristics of the Ca 2+ -inactivated conformation are downward conformation of the cytoplasmic assembly and tightly knit subunit interface contributed by a fully occupied Ca 2+ activation site, two inter-subunit resolved lipids, and two salt bridges between the EF hand domain and the S2–S3 loop validated by disease-causing mutations. The structural insight illustrates the prior Ca 2+ activation prerequisite for Ca 2+ inactivation and provides for a seamless transition from inactivated to closed conformations.","journal":"eLife","year":2022,"id":247170,"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":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":299021,"name":"Montserrat Samsó","orcid":"0000-0002-2788-3283","position":1,"is_corresponding":false},{"id":299018,"name":"Ashok R. Nayak","orcid":"0000-0001-9531-5168","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T00:23:53.369530Z","pmid":"35257661","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":[]}