{"doi":"10.1101/2022.12.29.522241","title":"Structural titration reveals Ca <sup>2+</sup> -dependent conformational landscape of the IP <sub>3</sub> receptor","abstract":"Summary Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are intracellular Ca 2+ -permeable cation channels whose biphasic dependence on cytoplasmic Ca 2+ gives rise to cytosolic Ca 2+ oscillations that regulate fertilization, cell division and cell death. Despite the critical roles of IP 3 R-mediated Ca 2+ oscillations, the structural underpinnings of the biphasic Ca 2+ dependence that underlies Ca 2+ oscillations are incompletely understood. Here, we collected images of an IP 3 R with Ca 2+ at concentrations spanning five orders of magnitude. Unbiased image analysis revealed that Ca 2+ binding does not explicitly induce conformational changes but rather biases a complex conformational landscape consisting of resting, preactivated, activated, and inhibited states. Using particle counts as a proxy for free energy, we demonstrate that Ca 2+ binding at a high-affinity site allows IP 3 Rs to activate by escaping a low-energy resting state through an ensemble of preactivated states. At high Ca 2+ , IP 3 Rs preferentially enter an inhibited state stabilized by a second, low-affinity Ca 2+ binding site. Together, these studies provide a mechanistic basis for the biphasic Ca 2+ -dependence of IP 3 R channel activity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":314116,"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":0.9502,"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":861867,"name":"Vinay Sapuru","orcid":"0000-0002-9699-6126","position":1,"is_corresponding":false},{"id":292045,"name":"Richard K. Hite","orcid":"0000-0003-0496-0669","position":2,"is_corresponding":false},{"id":292040,"name":"Navid Paknejad","orcid":"0000-0001-8914-7604","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":null,"created_at":"2026-07-19T00:33:48.490749Z","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":[]}