ArticleNature2012
Structural and functional conservation of key domains in InsP3 and ryanodine receptors.
Article in Nature, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
93 citing papers in PubMed, 170 citations in OpenAlex.
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- Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.The Journal of experimental medicine · 2025Article
- Calcium signals and potential therapy targets in ovarian cancer (Review).International journal of oncology · 2023Review
- Structural titration reveals CaNature communications · 2023Article
- Understanding IPCell calcium · 2023Review
- Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.Pflugers Archiv : European journal of physiology · 2023Article
- Conformational motions and ligand-binding underlying gating and regulation in IPNature communications · 2022Article
- Review
- Functional determination of calcium-binding sites required for the activation of inositol 1,4,5-trisphosphate receptors.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Recent Developments on the Roles of Calcium Signals and Potential Therapy Targets in Cervical Cancer.Cells · 2022Review
- Structural basis for activation and gating of IPNature communications · 2022Article
- RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation.Acta neuropathologica communications · 2021Article
- A Comparative Perspective on Functionally-Related, Intracellular Calcium Channels: The Insect Ryanodine and Inositol 1,4,5-Trisphosphate Receptors.Biomolecules · 2021Review
- The discovery and development of IP3 receptor modulators: an update.Expert opinion on drug discovery · 2021Article
- Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone.Frontiers in physiology · 2021Review
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- Retrieving functional pathways of biomolecules from single-particle snapshots.Nature communications · 2020Article
- Both d- and l-Glucose Polyphosphates Mimic d-Journal of medicinal chemistry · 2020Article
33 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca(2+) channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP(3)R gating is initiated by InsP(3) binding to the InsP(3)-binding core (IBC, residues 224-604 of InsP(3)R1) and it requires the suppressor domain (SD, residues 1-223 of InsP(3)R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP(3)R1 with (3.6 Å) and without (3.0 Å) InsP(3) bound. The arrangement of the three NT domains, SD, IBC-β and IBC-α, identifies two discrete interfaces (α and β) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP(3)R and of the ABC domains docked into RyR are remarkably similar. The importance of the α-interface for activation of InsP(3)R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP(3) causes partial closure of the clam-like IBC, disrupting the β-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP(3)R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP(3)R, and an InsP(3)R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP(3) and blocked by ryanodine. Activation mechanisms are conserved between InsP(3)R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-β or B domain), to gate the pore.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.