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- PDB-7t3t: IP3, ATP, and Ca2+ bound type 3 IP3 receptor in the active state -

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Basic information

Entry
Database: PDB / ID: 7t3t
TitleIP3, ATP, and Ca2+ bound type 3 IP3 receptor in the active state
ComponentsInositol 1,4,5-trisphosphate receptor type 3
KeywordsMETAL TRANSPORT / IP3 receptor / calcium signaling
Function / homology
Function and homology information


sensory perception of bitter taste / DAG and IP3 signaling / sensory perception of umami taste / inositol 1,3,4,5 tetrakisphosphate binding / inositol 1,4,5-trisphosphate-gated calcium channel activity / sensory perception of sweet taste / platelet dense tubular network membrane / Elevation of cytosolic Ca2+ levels / Effects of PIP2 hydrolysis / PLC beta mediated events ...sensory perception of bitter taste / DAG and IP3 signaling / sensory perception of umami taste / inositol 1,3,4,5 tetrakisphosphate binding / inositol 1,4,5-trisphosphate-gated calcium channel activity / sensory perception of sweet taste / platelet dense tubular network membrane / Elevation of cytosolic Ca2+ levels / Effects of PIP2 hydrolysis / PLC beta mediated events / inositol hexakisphosphate binding / inositol 1,4,5 trisphosphate binding / nuclear outer membrane / CLEC7A (Dectin-1) induces NFAT activation / intracellularly gated calcium channel activity / cytoplasmic side of endoplasmic reticulum membrane / brush border / Role of phospholipids in phagocytosis / calcium ion homeostasis / release of sequestered calcium ion into cytosol / Ion homeostasis / phosphatidylinositol binding / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / secretory granule membrane / sarcoplasmic reticulum / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / long-term synaptic potentiation / Regulation of insulin secretion / Sensory perception of sweet, bitter, and umami (glutamate) taste / memory / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / response to calcium ion / sensory perception of taste / apical part of cell / myelin sheath / Ca2+ pathway / positive regulation of cytosolic calcium ion concentration / receptor complex / G protein-coupled receptor signaling pathway / neuronal cell body / calcium ion binding / endoplasmic reticulum membrane / nucleolus / endoplasmic reticulum / nucleoplasm / membrane / 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 ...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 / MIR domain profile. / Domain in ryanodine and inositol trisphosphate receptors and protein O-mannosyltransferases / Mir domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE / Inositol 1,4,5-trisphosphate receptor type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSchmitz, E.A. / Takahashi, H. / Karakas, E.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM141251 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)P30DK020593 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM008320 United States
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis for activation and gating of IP receptors.
Authors: Emily A Schmitz / Hirohide Takahashi / Erkan Karakas /
Abstract: A pivotal component of the calcium (Ca) signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP) receptor (IPR), which mediates Ca release from the endoplasmic reticulum (ER), controlling ...A pivotal component of the calcium (Ca) signaling toolbox in cells is the inositol 1,4,5-triphosphate (IP) receptor (IPR), which mediates Ca release from the endoplasmic reticulum (ER), controlling cytoplasmic and organellar Ca concentrations. IPRs are co-activated by IP and Ca, inhibited by Ca at high concentrations, and potentiated by ATP. However, the underlying molecular mechanisms are unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human type-3 IPR obtained from a single dataset in multiple gating conformations: IP-ATP bound pre-active states with closed channels, IP-ATP-Ca bound active state with an open channel, and IP-ATP-Ca bound inactive state with a closed channel. The structures demonstrate how IP-induced conformational changes prime the receptor for activation by Ca, how Ca binding leads to channel opening, and how ATP modulates the activity, providing insights into the long-sought questions regarding the molecular mechanism underpinning receptor activation and gating.
History
DepositionDec 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Inositol 1,4,5-trisphosphate receptor type 3
B: Inositol 1,4,5-trisphosphate receptor type 3
C: Inositol 1,4,5-trisphosphate receptor type 3
D: Inositol 1,4,5-trisphosphate receptor type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,201,43520
Polymers1,197,3044
Non-polymers4,13116
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Inositol 1,4,5-trisphosphate receptor type 3 / IP3 receptor isoform 3 / IP3R 3 / InsP3R3 / Type 3 inositol 1 / 4 / 5-trisphosphate receptor / Type ...IP3 receptor isoform 3 / IP3R 3 / InsP3R3 / Type 3 inositol 1 / 4 / 5-trisphosphate receptor / Type 3 InsP3 receptor


Mass: 299325.875 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITPR3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14573
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-I3P / D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE / Inositol trisphosphate


Mass: 420.096 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H15O15P3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


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
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Inositol 1,4,5-trisphosphate receptor type 3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 1.2 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
Details: IP3, ATP, and CaCl2 were added before cryo-grid preparation.
Buffer component
IDConc.NameFormulaBuffer-ID
10.2 MSodium ChlorideNaClSodium chloride1
20.02 MTris-HClTris1
31 mMEDTAEthylenediaminetetraacetic acid1
42 mMTCEP1
50.005 %Lauryl neopentyl glycol1
60.005 %glyco-diosgenin1
75 mMATPAdenosine triphosphate1
80.5 mMinositol 1,4,5-triphosphateIP31
90.1 mMCalcium chlorideCaCl21
SpecimenConc.: 1.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 4 / Num. of real images: 42361

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Processing

EM software
IDNameCategory
2SerialEMimage acquisition
3EPUimage acquisition
5GctfCTF correction
8Cootmodel fitting
10PHENIXmodel refinement
11RELIONinitial Euler assignment
12cryoSPARCfinal Euler assignment
13RELIONclassification
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 20039 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6UQK

6uqk

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