{"doi":"10.1101/2021.10.18.464806","title":"Structural basis for activation and gating of IP <sub>3</sub> receptors","abstract":"Abstract Calcium (Ca 2+ ) is a universal and versatile cellular messenger used to regulate numerous cellular processes in response to external or internal stimuli. A pivotal component of the Ca 2+ signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP 3 ) receptors (IP 3 Rs), which mediate Ca 2+ release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca 2+ concentrations 1-3 . IP 3 Rs are activated by IP 3 and Ca 2+ , inhibited by Ca 2+ at high concentrations, and potentiated by ATP 1-3 . However, the underlying molecular mechanisms are unclear due to the lack of structures in the active conformation. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IP 3 R in multiple gating conformations; IP 3 -ATP bound pre-active states with closed channels, IP 3 -ATP-Ca 2+ bound active state with an open channel, and IP 3 -ATP-Ca 2+ bound inactive state with a closed channel. The structures demonstrate how IP 3 -induced conformational changes prime the receptor for activation by Ca 2+ , how Ca 2+ binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism of the receptor activation and gating.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":227057,"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":0.9627,"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":830862,"name":"Hirohide Takahashi","orcid":"0000-0002-2553-8806","position":1,"is_corresponding":false},{"id":467089,"name":"Erkan Karakaş","orcid":"0000-0001-6552-3185","position":2,"is_corresponding":false},{"id":830861,"name":"Emily A. Schmitz","orcid":"0000-0002-5122-8991","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:54:42.179886Z","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":[]}