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- PDB-12ai: Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate recept... -

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Basic information

Entry
Database: PDB / ID: 12ai
TitleStructure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptor (IP3R2) in the presence of IP3/Ca2+/ATP
ComponentsInositol 1,4,5-trisphosphate-gated calcium channel ITPR2
KeywordsMEMBRANE PROTEIN / ion channel
Function / homology
Function and homology information


Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / inositol 1,4,5-trisphosphate-gated calcium channel activity / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Ion homeostasis / inositol 1,4,5 trisphosphate binding / cellular response to ethanol / transport vesicle membrane / intracellularly gated calcium channel activity ...Effects of PIP2 hydrolysis / Elevation of cytosolic Ca2+ levels / inositol 1,4,5-trisphosphate-gated calcium channel activity / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Ion homeostasis / inositol 1,4,5 trisphosphate binding / cellular response to ethanol / transport vesicle membrane / intracellularly gated calcium channel activity / release of sequestered calcium ion into cytosol / cellular response to cAMP / sarcoplasmic reticulum membrane / phosphatidylinositol binding / secretory granule membrane / sarcoplasmic reticulum / calcium ion transport / scaffold protein binding / cell cortex / response to hypoxia / transmembrane transporter binding / signaling receptor complex / axon / calcium ion binding / endoplasmic reticulum membrane / endoplasmic reticulum / ATP 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 ...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 / Armadillo-type fold
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE / Chem-PLX / Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsSerysheva, I.I. / Baker, M.R. / Fan, G.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM153178 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM153178-01S1 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM072804 United States
American Heart Association23CDA1048883 United States
Welch FoundationAU-2014-20220331 United States
Welch FoundationAU-2014-20250403 United States
CitationJournal: Nat Commun / Year: 2026
Title: Cryo-EM insights into isoform-specific properties of the IPR2 channel.
Authors: Mariah R Baker / Xiaoxuan Lin / Guizhen Fan / Ariel Martinez-Chavez / Larry E Wagner / Sundeep Malik / Tyler Allison / Briar Bell / Alexander B Seryshev / Julio Cordero-Morales / Matthew L ...Authors: Mariah R Baker / Xiaoxuan Lin / Guizhen Fan / Ariel Martinez-Chavez / Larry E Wagner / Sundeep Malik / Tyler Allison / Briar Bell / Alexander B Seryshev / Julio Cordero-Morales / Matthew L Baker / David I Yule / Irina I Serysheva /
Abstract: Calcium release through inositol 1,4,5-trisphosphate receptors (IPRs) is a fundamental signaling mechanism that regulates diverse cellular processes. Among the three mammalian IPR isoforms, IPR2 is ...Calcium release through inositol 1,4,5-trisphosphate receptors (IPRs) is a fundamental signaling mechanism that regulates diverse cellular processes. Among the three mammalian IPR isoforms, IPR2 is widely expressed, yet its structural basis for activation and regulation remains unclear. Here, we report cryo-EM structures of mammalian IPR2 in ligand-free (closed) and CaIP/ATP-bound (activated) states at 3.3 Å and 3.6 Å resolution, respectively. These structures define the architecture of IPR2 and reveal conformational transitions associated with channel activation. Although the IP-binding pocket is conserved, subtype-specific differences in IP affinity likely arise from conformational dynamics of the regulatory ARM2 domain. Comparative analyses of IPR isoforms identify subtype-specific allosteric networks and domain motions that underlie differential regulation. We further define the ATP-binding site and, through mutagenesis and electrophysiology, establish the structural basis for ATP modulation of channel activity. Together, these findings reveal mechanisms of IPR2 activation and subtype-specific regulation, providing a framework for understanding isoform-dependent Ca signaling.
History
DepositionMar 23, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata
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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-gated calcium channel ITPR2
B: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
C: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
D: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,238,61824
Polymers1,231,4194
Non-polymers7,20020
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2 / IP3 receptor isoform 2 / IP3R 2 / InsP3R2 / Inositol 1 / 4 / 5-trisphosphate receptor type 2 / 5- ...IP3 receptor isoform 2 / IP3R 2 / InsP3R2 / Inositol 1 / 4 / 5-trisphosphate receptor type 2 / 5-trisphosphate type V receptor / Type 2 inositol 1 / 5-trisphosphate receptor / Type 2 InsP3 receptor


Mass: 307854.719 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Itpr2, Itpr5 / Cell line (production host): HEK293S GNTI- / Production host: Homo sapiens (human) / References: UniProt: Q9Z329

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Non-polymers , 5 types, 20 molecules

#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-ATP / ADENOSINE-5'-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
#4: Chemical
ChemComp-I3P / D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE


Mass: 420.096 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H15O15P3 / Feature type: SUBJECT OF INVESTIGATION
#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
#6: Chemical
ChemComp-PLX / (9R,11S)-9-({[(1S)-1-HYDROXYHEXADECYL]OXY}METHYL)-2,2-DIMETHYL-5,7,10-TRIOXA-2LAMBDA~5~-AZA-6LAMBDA~5~-PHOSPHAOCTACOSANE-6,6,11-TRIOL


Mass: 767.132 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H89NO8P / Comment: phospholipid*YM

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Details

Has ligand of interestY
Has protein modificationY

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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 2 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 1.2 MDa / Experimental value: YES
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 GNTI- / Plasmid: BacMam
Buffer solutionpH: 7.4 / Details: 50mM Tris-HCl, 150 mM NaCl, 1mM DTT, 1mM EDTA
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: immuoaffinity purified, LMNG and lipid solubilized tetrameric ion channel protein
Specimen supportGrid material: COPPER / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Calibrated magnification: 46100 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recording

Imaging-ID: 1 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 37329

IDAverage exposure time (sec.)Electron dose (e/Å2)Detector mode
181.43SUPER-RESOLUTION
271.66SUPER-RESOLUTION
381.43
Image scans
Movie frames/imageUsed frames/imageIDImage recording-IDEntry-ID
351-351112AI
301-302212AI
351-353312AI

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC4.7particle selectionblob and template picker
2EPUimage acquisition
4cryoSPARC4.7CTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10cryoSPARC4.7initial Euler assignment
11cryoSPARC4.7final Euler assignment
12cryoSPARC4.7classification
13cryoSPARC4.73D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6026377
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151391 / Symmetry type: POINT
Atomic model buildingB value: 135.9 / Protocol: FLEXIBLE FIT / Space: REAL / Target criteria: fit to map
Atomic model buildingSource name: AlphaFold / Type: in silico model

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