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- EMDB-76260: Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate recept... -

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Entry
Database: EMDB / ID: EMD-76260
TitleStructure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptors (IP3R2) in the Apo-state
Map dataApo-IP3R2_half
Sample
  • Organelle or cellular component: Inositol 1,4,5-trisphosphate receptor type 2
    • Protein or peptide: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
  • Ligand: ZINC ION
  • Ligand: (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
Keywordsion channel / MEMBRANE PROTEIN
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
Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsSerysheva II / Baker MR / Fan G
Funding support United States, 6 items
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 22, 2026-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateSep 9, 2026-
Current statusSep 9, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76260.png

Downloads & links

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Map

FileDownload / File: emd_76260.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationApo-IP3R2_half
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 440 pix.
= 475.2 Å		1.08 Å/pix.
x 440 pix.
= 475.2 Å		1.08 Å/pix.
x 440 pix.
= 475.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.273
Minimum - Maximum-1.0977752 - 2.1501696
Average (Standard dev.)0.0031052134 (±0.058762364)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 475.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Apo-IP3R2 half B

Fileemd_76260_half_map_1.map
AnnotationApo-IP3R2_half B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Apo-IP3R2 half A

Fileemd_76260_half_map_2.map
AnnotationApo-IP3R2_half A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Inositol 1,4,5-trisphosphate receptor type 2

EntireName: Inositol 1,4,5-trisphosphate receptor type 2
Components
  • Organelle or cellular component: Inositol 1,4,5-trisphosphate receptor type 2
    • Protein or peptide: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
  • Ligand: ZINC ION
  • Ligand: (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

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Supramolecule #1: Inositol 1,4,5-trisphosphate receptor type 2

SupramoleculeName: Inositol 1,4,5-trisphosphate receptor type 2 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 1.2 MDa

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Macromolecule #1: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2

MacromoleculeName: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 307.85375 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSDKMSSFLY IGDIVSLYAE GSVNGFISTL GLVDDRCVVH PEAGDLANPP KKFRDCLFKV CPMNRYSAQK QYWKAKQAKQ GNHTEAALL KKLQHAAELE QKQNESENRK LLGEIVKYSN VIQLLHIKSN KYLTVNKRLP ALLEKNAMRV SLDAAGNEGS W FYIHPFWK ...String:
MSDKMSSFLY IGDIVSLYAE GSVNGFISTL GLVDDRCVVH PEAGDLANPP KKFRDCLFKV CPMNRYSAQK QYWKAKQAKQ GNHTEAALL KKLQHAAELE QKQNESENRK LLGEIVKYSN VIQLLHIKSN KYLTVNKRLP ALLEKNAMRV SLDAAGNEGS W FYIHPFWK LRSEGDNIVV GDKVVLMPVN AGQPLHASNV ELLDNPGCKE VNAVNCNTSW KITLFMKFSS YREDVLKGGD VV RLFHAEQ EKFLTCDDYE KKQHIFLRTT LRQSATSATS SKALWEIEVV HHDPCRGGAG QWNSLFRFKH LATGNYLAAE LNP DYRDAQ NEGKNVKDGE IPTPKKKRQA GEKIMYTLVS VPHGNDIASL FELDATTLQR ADCLVPRNSY VRLRHLCTNT WVTS TTIPI DTEEERPVML KIGTCQTKED KEAFAIVCVP LSEVRDLDFA NDANKVLATT VKKLENGSIT QNERRFVTKL LEDLI FFVA DVTNNGQDVL DVVITKPNRE RQKLMREQNI LAQVFGILKA PFKEKAGEGS MLRLEDLGDQ RYAPYKYVLR LCYRVL RHS QQDYRKNQEY IAKNFCVMQS QIGYDILAED TITALLHNNR KLLEKHITAK EIETFVSLLR RNREPRFLDY LSDLCVS NS TAIPVTQELI CKFMLSPGNA DILIQTKLVS MQVENPMESS ILPDDIDDEE VWLYWIDSNK EPHGKAIRHL AQEAREGT K ADLEVLTYYR YQLNLFARMC LDRQYLAINQ ISTQLSVDLI LRCVSDESLP FDLRASFCRL MLHMHVDRDP QESVVPVRY ARLWTEIPTK ITIHEYDSIT DSSRNDMKRK FALTMEFVEE YLKEVVNQPF PFGDKEKNKL TFEVVHLARN LIYFGFYSFS ELLRLTRTL LAILDIVQAP MSSYFERLSK FQDGSNNVMR TIHGVGEMMT QMVLSRGSIF PVSVPDAQPI VHPSKQASPG E QEDVTVMD TKLKVIEILQ FILSVRLDYR ISYMLSIYKK EFGDNNDNGD PSASGTPDTL LPSALVPDID EIAAQAETMF AG RKEKTPV QLDDEGGRTF LRVLIHLIMH DYAPLLSGAL QLLFKHFSQR AEVLQAFKQV QLLVSNQDVD NYKQIKADLD QLR LTVEKS ELWVEKSGSY ENGDVGEGQA KGGEEANEES NLLSPVQDGA KTPQIDSNKG NNYRIVKEIL IRLSKLCVQN KKCR NQHQR LLKNMGAHSV VLDLLQIPYE KTDEKMNEVM DLAHTFLQNF CRGNPQNQVL LHKHLNLFLT PGLLEAETMR HIFMN NYHL CNEISERVVQ HFVHCIETHG RHVEYLRFLQ TIVKADGKYV KKCQDMVMTE LINGGEDVLI FYNDRASFPI LLNMMC SER ARGDESGPLA YHITLVELLA ACTEGKNVYT EIKCNSLLPL DDIVRVVTHD DCIPEVKIAY VNFVNHCYVD TEVEMKE IY TSNHIWKLFE NFLVDMARVC NTTTDRKHAD TFLERCVTES VMNIVSGFFN SPFSDNSTSL QTHQPVFIQL LQSAFRIY N CTWPNPAQKA SVESCIRALA EVAKNRGIAI PVDLDSQVNT LFMKNHSSTV QRAAMGWRLS ARSGPRFKEA LGGPAWDYR NIIEKLQDVV ASLEQQFSPM MQAEFSVLVD VLYSPELLFP EGSDARIRCG AFMSKLINHT KKLMEKEEKL CIKILQTLRE MLEKKDSFM EEGSTLRRIL LNRYFKGDHS ISVNGPLSGA YAKTAQVGGS FSGQDSDKKG ISMSDIQCLL DKEGASELVI D VIVNTKND RIFSEGILLG IALLEGGNTQ TQYSFYQQLH EQKKSEKFFK VLYDRMKAAQ KEIRSTVTVN TIDLGSKKRE ED SDVMALG PRMRVRDSSL HLREGMKGQL TEASSATSKA YCVYRREMDP EIDTMCPGQE AGSAEEKSAE EVTMSPAITI MRP ILRFLQ LLCENHNREL QNFLRNQNNK TNYNLVCETL QFLDCICGST TGGLGLLGLY INERNVALVN QTLESLTEYC QGPC HENQT CIATHESNGI DIIIALILND INPLGKYRMD LVLQLKNNAS KLLLAIMESR HDSENAERIL FNMRPRELVD VMKNA YNQG LECDHGDEEG GDDGVSPKDV GHNIYILAHQ LARHNKLLQQ MLKPGSDPEE GDEALKYYAN HTAQIEIVRH DRTMEQ IVF PVPNICEFLT RESKYRVFNT TERDEQGSKV NDFFQQTEDL YNEMKWQKKI RNNPALFWFS RHISLWGSIS FNLAVFI NL AVALFYPFGD DGDEGTLSPM FSVLLWVAVA ICTSMLFFFS KPVGIRPFLV SVMLRSIYTI GLGPTLILLG AANLCNKI V FLVSFVGNRG TFTRGYRAVI LDMAFLYHVA YVLVCMLGLF VHEFFYSFLL FDLVYREETL LNVIKSVTRN GRSIILTAV LALILVYLFS IIGFLFLKDD FTMEVDRLKN RTPVTGNHGV PTMTLSSMME TCQKENCSPT IPSSNTAGEE GEDGIERTCD TLLMCIVTV LNQGLRNGGG VGDVLRRPSK DEPLFAARVV YDLLFFFIVI IIVLNLIFGV IIDTFADLRS EKQKKEEILK T TCFICGLE RDKFDNKTVS FEEHIKSEHN MWHYLYFIVL VKVKDPTEYT GPESYVAQMI TEKNLDWFPR MRAMSLVSNE GD SEQNEIR NLQEKLESTM SLVKQLSGQL AELKEQMTEQ RKNKQRLGFL GSNTPHVNHH MPPH

UniProtKB: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #3: (9R,11S)-9-({[(1S)-1-HYDROXYHEXADECYL]OXY}METHYL)-2,2-DIMETHYL-5,...

MacromoleculeName: (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
type: ligand / ID: 3 / Number of copies: 20 / Formula: PLX
Molecular weightTheoretical: 767.132 Da
Chemical component information

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 / phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3 mg/mL
BufferpH: 7.4 / Details: 50mM Tris-HCl, 150 mM NaCl, 1mM DTT, 1mM EDTA
GridModel: Quantifoil / Material: COPPER / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 10 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Detailsimmuoaffinity purified, LMNG and lipid solubilized tetrameric ion channel protein

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-35 / Number grids imaged: 1 / Number real images: 8112 / Average electron dose: 1.43 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 46100 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 413650
CTF correctionSoftware - Name: cryoSPARC (ver. 4.7) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7) / Number images used: 73731
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 153.41 / Target criteria: fit to density
Output model

PDB-12ad:
Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptors (IP3R2) in the Apo-state

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