|Entry||Database: PDB / ID: 8ear|
|Title||Structure of the full-length IP3R1 channel determined in the presence of Calcium/IP3/ATP|
|Components||Inositol 1,4,5-trisphosphate receptor type 1|
|Keywords||MEMBRANE PROTEIN / Calcium channel / lipid nanodisc|
|Function / homology|
Function and homology information
Effects of PIP2 hydrolysis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / inositol 1,4,5-trisphosphate receptor activity involved in regulation of postsynaptic cytosolic calcium levels / Elevation of cytosolic Ca2+ levels / cGMP effects / smooth endoplasmic reticulum membrane / platelet dense granule membrane / platelet dense tubular network / inositol phosphate-mediated signaling / negative regulation of calcium-mediated signaling ...Effects of PIP2 hydrolysis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / inositol 1,4,5-trisphosphate receptor activity involved in regulation of postsynaptic cytosolic calcium levels / Elevation of cytosolic Ca2+ levels / cGMP effects / smooth endoplasmic reticulum membrane / platelet dense granule membrane / platelet dense tubular network / inositol phosphate-mediated signaling / negative regulation of calcium-mediated signaling / inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / epithelial fluid transport / calcineurin complex / regulation of postsynaptic cytosolic calcium ion concentration / voluntary musculoskeletal movement / inositol 1,4,5 trisphosphate binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / endoplasmic reticulum calcium ion homeostasis / positive regulation of calcium ion transport / positive regulation of hepatocyte proliferation / transport vesicle membrane / nuclear inner membrane / calcium-release channel activity / Ion homeostasis / dendrite development / GABA-ergic synapse / release of sequestered calcium ion into cytosol / calcium channel inhibitor activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / liver regeneration / phosphatidylinositol binding / post-embryonic development / sarcoplasmic reticulum / secretory granule membrane / synaptic membrane / positive regulation of neuron projection development / cellular response to cAMP / Schaffer collateral - CA1 synapse / calcium-mediated signaling / negative regulation of neuron death / presynapse / cell morphogenesis / cytoplasmic vesicle membrane / calcium ion transport / nuclear envelope / postsynapse / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / transmembrane transporter binding / protein phosphatase binding / : / response to hypoxia / postsynaptic density / positive regulation of apoptotic process / membrane raft / protein domain specific binding / intracellular membrane-bounded organelle / synapse / neuronal cell body / dendrite / protein-containing complex binding / nucleolus / calcium ion binding / endoplasmic reticulum membrane / perinuclear region of cytoplasm / endoplasmic reticulum / protein-containing complex / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Inositol 1,4,5-trisphosphate receptor / RyR/IP3 receptor binding core, RIH domain superfamily / RyR/IP3R Homology associated domain / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / RyR and IP3R Homology associated / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / MIR motif / Mir domain superfamily ...Inositol 1,4,5-trisphosphate receptor / RyR/IP3 receptor binding core, RIH domain superfamily / RyR/IP3R Homology associated domain / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / RyR and IP3R Homology associated / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / MIR motif / Mir domain superfamily / MIR domain / MIR domain profile. / Domain in ryanodine and inositol trisphosphate receptors and protein O-mannosyltransferases / Ion transport domain / Ion transport protein / Armadillo-type fold
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE / Chem-PLX / Inositol 1,4,5-trisphosphate receptor type 1
Similarity search - Component
|Biological species||Rattus norvegicus (Norway rat)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å|
|Authors||Fan, G. / Baker, M.R. / Terry, L.E. / Arige, V. / Chen, M. / Seryshev, A.B. / Baker, M.L. / Ludtke, S.J. / Yule, D.I. / Serysheva, I.I.|
|Funding support|| United States, 7items |
|Citation||Journal: Nat Commun / Year: 2022|
Title: Conformational motions and ligand-binding underlying gating and regulation in IPR channel.
Authors: Guizhen Fan / Mariah R Baker / Lara E Terry / Vikas Arige / Muyuan Chen / Alexander B Seryshev / Matthew L Baker / Steven J Ludtke / David I Yule / Irina I Serysheva /
Abstract: Inositol-1,4,5-trisphosphate receptors (IPRs) are activated by IP and Ca and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single ...Inositol-1,4,5-trisphosphate receptors (IPRs) are activated by IP and Ca and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IPR1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP, Ca and ATP, revealing conformational changes that couple ligand-binding to channel opening. Using a deep-learning approach and 3D variability analysis we extracted molecular motions of the key protein domains from cryo-EM density data. We find that IP binding relies upon intrinsic flexibility of the ARM2 domain in the tetrameric channel. Our results highlight a key role of dynamic side chains in regulating gating behavior of IPR channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel.
|Structure viewer||Molecule: |
Downloads & links
A: Inositol 1,4,5-trisphosphate receptor type 1
B: Inositol 1,4,5-trisphosphate receptor type 1
C: Inositol 1,4,5-trisphosphate receptor type 1
D: Inositol 1,4,5-trisphosphate receptor type 1
-Protein , 1 types, 4 molecules A
B C D
Mass: 313657.406 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Rattus norvegicus (Norway rat) / Organ: cerebellum / References: UniProt: P29994
-Non-polymers , 5 types, 56 molecules
Mass: 507.181 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
Mass: 420.096 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H15O15P3 / Feature type: SUBJECT OF INVESTIGATION
Mass: 40.078 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
ChemComp-PLX / (
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Type 1 inositol 1,4,5-trisphosphate receptor tetrameric protein complex|
Type: COMPLEX / Entity ID: #1 / Source: NATURAL
|Molecular weight||Value: 1.3 MDa / Experimental value: NO|
|Source (natural)||Organism: Rattus norvegicus (Norway rat) / Cellular location: membrane / Organ: cerebellum / Organelle: endoplasmic reticulum|
|Buffer solution||pH: 7.4|
|Specimen||Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: reconstituted in lipid nanodisc|
|Specimen support||Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/1|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: TFS KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Calibrated magnification: 46943 X / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE|
|Specimen holder||Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER|
|Image recording||Average exposure time: 0.2 sec. / Electron dose: 49 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of real images: 24478|
|EM imaging optics||Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV|
|Image scans||Sampling size: 5 µm / Width: 3840 / Height: 3712 / Movie frames/image: 35|
|CTF correction||Type: NONE|
|Particle selection||Num. of particles selected: 1452797 / Details: NeuralNet autopicking in EMAN2|
|Symmetry||Point symmetry: C4 (4 fold cyclic)|
|3D reconstruction||Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 133740 / Symmetry type: POINT|
|Atomic model building||Protocol: FLEXIBLE FIT / Space: REAL|
|Atomic model building||PDB-ID: 7LHE|
|Refine LS restraints|
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