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- EMDB-9243: Structure of full-length IP3R1 channel bound with Adenophostin A ... -

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Basic information

Entry
Database: EMDB / ID: EMD-9243
TitleStructure of full-length IP3R1 channel bound with Adenophostin A (composite)
Map datacryo-EM density map (composite) of IP3R1 in ligand-bound state
Sample
  • Complex: Inositol 1,4,5-trisphosphate receptor
    • Protein or peptide: Inositol 1,4,5-trisphosphate receptor type 1
  • Ligand: Adenophostin A
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 / release of sequestered calcium ion into cytosol by endoplasmic reticulum / cGMP effects / smooth endoplasmic reticulum membrane / Elevation of cytosolic Ca2+ levels / platelet dense tubular network / calcineurin complex / platelet dense granule membrane ...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 / release of sequestered calcium ion into cytosol by endoplasmic reticulum / cGMP effects / smooth endoplasmic reticulum membrane / Elevation of cytosolic Ca2+ levels / platelet dense tubular network / calcineurin complex / platelet dense granule membrane / epithelial fluid transport / ion channel modulating, G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / inositol 1,4,5-trisphosphate-gated calcium channel activity / calcium import into the mitochondrion / voluntary musculoskeletal movement / inositol 1,4,5 trisphosphate binding / negative regulation of calcium-mediated signaling / positive regulation of calcium ion transport / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / endoplasmic reticulum calcium ion homeostasis / positive regulation of hepatocyte proliferation / nuclear inner membrane / Ion homeostasis / transport vesicle membrane / dendrite development / ligand-gated ion channel signaling pathway / intracellularly gated calcium channel activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / single fertilization / calcium channel inhibitor activity / GABA-ergic synapse / cellular response to cAMP / release of sequestered calcium ion into cytosol / regulation of cytosolic calcium ion concentration / phosphatidylinositol binding / post-embryonic development / secretory granule membrane / sarcoplasmic reticulum / synaptic membrane / liver regeneration / cell morphogenesis / positive regulation of insulin secretion / Schaffer collateral - CA1 synapse / positive regulation of neuron projection development / calcium ion transport / nuclear envelope / presynapse / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / protein phosphatase binding / protein homotetramerization / transmembrane transporter binding / postsynapse / postsynaptic density / response to hypoxia / positive regulation of apoptotic process / protein domain specific binding / neuronal cell body / calcium ion binding / dendrite / synapse / endoplasmic reticulum membrane / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / perinuclear region of cytoplasm / endoplasmic reticulum / protein-containing complex / ATP binding / identical protein binding / 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 / Armadillo-type fold
Similarity search - Domain/homology
Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Rat (rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsSerysheva II / Fan G / Baker MR / Wang Z / Seryshev A / Ludtke SJ / Baker ML
Funding support United States, 6 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM072804 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R21AR063255 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R21NS106968 United States
American Heart Association16GRNT2972000 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM080139 United States
National Science Foundation (NSF, United States)DBI-1356306 United States
CitationJournal: Cell Res / Year: 2018
Title: Cryo-EM reveals ligand induced allostery underlying InsPR channel gating.
Authors: Guizhen Fan / Mariah R Baker / Zhao Wang / Alexander B Seryshev / Steven J Ludtke / Matthew L Baker / Irina I Serysheva /
Abstract: Inositol-1,4,5-trisphosphate receptors (InsPRs) are cation channels that mobilize Ca from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsPR activation is the ...Inositol-1,4,5-trisphosphate receptors (InsPRs) are cation channels that mobilize Ca from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsPR activation is the coupled interplay between binding of InsP and Ca that switches the ion conduction pathway between closed and open states to enable the passage of Ca through the channel. However, the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown. Here, we present the electron cryo-microscopy structure of InsPR1 from rat cerebellum determined to 4.1 Å resolution in the presence of activating concentrations of Ca and adenophostin A (AdA), a structural mimetic of InsP and the most potent known agonist of the channel. Comparison with the 3.9 Å-resolution structure of InsPR1 in the Apo-state, also reported herein, reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate. Together, our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsPR channel.
History
DepositionOct 22, 2018-
Header (metadata) releaseNov 14, 2018-
Map releaseDec 5, 2018-
UpdateNov 27, 2019-
Current statusNov 27, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.75
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 1.75
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6mu1
  • Surface level: 1.75
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9243.png

Downloads & links

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Map

FileDownload / File: emd_9243.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM density map (composite) of IP3R1 in ligand-bound state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.26 Å/pix.
x 200 pix.
= 252. Å		1.26 Å/pix.
x 200 pix.
= 252. Å		1.26 Å/pix.
x 200 pix.
= 252. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.26 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.75 / Movie #1: 1.75
Minimum - Maximum-13.204424 - 16.041422
Average (Standard dev.)0.09182708 (±0.6318866)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 252.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.261.261.26
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z252.000252.000252.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ450450450
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-13.20416.0410.092

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Supplemental data

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Sample components

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Entire : Inositol 1,4,5-trisphosphate receptor

EntireName: Inositol 1,4,5-trisphosphate receptor
Components
  • Complex: Inositol 1,4,5-trisphosphate receptor
    • Protein or peptide: Inositol 1,4,5-trisphosphate receptor type 1
  • Ligand: Adenophostin A

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

SupramoleculeName: Inositol 1,4,5-trisphosphate receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: tetrameric assembly
Source (natural)Organism: Rattus norvegicus (Norway rat) / Organ: Brain / Tissue: Cerebellum / Organelle: endoplasmic reticulum / Location in cell: membrane
Molecular weightTheoretical: 1.3 MDa

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Macromolecule #1: Inositol 1,4,5-trisphosphate receptor type 1

MacromoleculeName: Inositol 1,4,5-trisphosphate receptor type 1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rat (rat)
Molecular weightTheoretical: 312.442 KDa
SequenceString: MSDKMSSFLH IGDICSLYAE GSTNGFISTL GLVDDRCVVQ PEAGDLNNPP KKFRDCLFKL CPMNRYSAQK QFWKAAKPGA NSTTDAVLL NKLHHAADLE KKQNETENRK LLGTVIQYGN VIQLLHLKSN KYLTVNKRLP ALLEKNAMRV TLDEAGNEGS W FYIQPFYK ...String:
MSDKMSSFLH IGDICSLYAE GSTNGFISTL GLVDDRCVVQ PEAGDLNNPP KKFRDCLFKL CPMNRYSAQK QFWKAAKPGA NSTTDAVLL NKLHHAADLE KKQNETENRK LLGTVIQYGN VIQLLHLKSN KYLTVNKRLP ALLEKNAMRV TLDEAGNEGS W FYIQPFYK LRSIGDSVVI GDKVVLNPVN AGQPLHASSH QLVDNPGCNE VNSVNCNTSW KIVLFMKWSD NKDDILKGGD VV RLFHAEQ EKFLTCDEHR KKQHVFLRTT GRQSATSATS SKALWEVEVV QHDPCRGGAG YWNSLFRFKH LATGHYLAAE VDP DFEEEC LEFQPSVDPD QDASRSRLRN AQEKMVYSLV SVPEGNDISS IFELDPTTLR GGDSLVPRNS YVRLRHLCTN TWVH STNIP IDKEEEKPVM LKIGTSPLKE DKEAFAIVPV SPAEVRDLDF ANDASKVLGS IAGKLEKGTI TQNERRSVTK LLEDL VYFV TGGTNSGQDV LEVVFSKPNR ERQKLMREQN ILKQIFKLLQ APFTDCGDGP MLRLEELGDQ RHAPFRHICR LCYRVL RHS QQDYRKNQEY IAKQFGFMQK QIGYDVLAED TITALLHNNR KLLEKHITAA EIDTFVSLVR KNREPRFLDY LSDLCVS MN KSIPVTQELI CKAVLNPTNA DILIETKLVL SRFEFEGVST GENALEAGED EEEVWLFWRD SNKEIRSKSV RELAQDAK E GQKEDRDVLS YYRYQLNLFA RMCLDRQYLA INEISGQLDV DLILRCMSDE NLPYDLRASF CRLMLHMHVD RDPQEQVTP VKYARLWSEI PSEIAIDDYD SSGASKDEIK ERFAQTMEFV EEYLRDVVCQ RFPFSDKEKN KLTFEVVNLA RNLIYFGFYN FSDLLRLTK ILLAILDCVH VTTIFPISKM TKGEENKGSN VMRSIHGVGE LMTQVVLRGG GFLPMTPMAA APEGNVKQAE P EKEDIMVM DTKLKIIEIL QFILNVRLDY RISCLLCIFK REFDESNSQS SETSSGNSSQ EGPSNVPGAL DFEHIEEQAE GI FGGSEEN TPLDLDDHGG RTFLRVLLHL TMHDYPPLVS GALQLLFRHF SQRQEVLQAF KQVQLLVTSQ DVDNYKQIKQ DLD QLRSIV EKSELWVYKG QGPDEPMDGA SGENEHKKTE EGTSKPLKHE STSSYNYRVV KEILIRLSKL CVQESASVRK SRKQ QQRLL RNMGAHAVVL ELLQIPYEKA EDTKMQEIMR LAHEFLQNFC AGNQQNQALL HKHINLFLNP GILEAVTMQH IFMNN FQLC SEINERVVQH FVHCIETHGR NVQYIKFLQT IVKAEGKFIK KCQDMVMAEL VNSGEDVLVF YNDRASFQTL IQMMRS ERD RMDENSPLFM YHIHLVELLA VCTEGKNVYT EIKCNSLLPL DDIVRVVTHE DCIPEVKIAY INFLNHCYVD TEVEMKE IY TSNHMWKLFE NFLVDICRAC NNTSDRKHAD SVLEKYVTEI VMSIVTTFFS SPFSDQSTTL QTRQPVFVQL LQGVFRVY H CNWLMPSQKA SVESCIRVLS DVAKSRAIAI PVDLDSQVNN LFLKSHNIVQ KTAMNWRLSA RNAARRDSVL AASRDYRNI IERLQDIVSA LEDRLRPLVQ AELSVLVDVL HRPELLFPEN TDARRKCESG GFICKLIKHT KQLLEENEEK LCIKVLQTLR EMMTKDRGY GEKQISIDEL ENAELPQPPE AENSTEQELE PSPPLRQLED HKRGEALRQI LVNRYYGNIR PSGRRESLTS F GNGPLSPG GPSKPGGGGG GPGSGSTSRG EMSLAEVQCH LDKEGASNLV IDLIMNASSD RVFHESILLA IALLEGGNTT IQ HSFFCRL TEDKKSEKFF KVFYDRMKVA QQEIKATVTV NTSDLGNKKK DDEVDRDAPS RKKAKEPTTQ ITEEVRDQLL EAS AATRKA FTTFRREADP DDHYQSGEGT QATTDKAKDD LEMSAVITIM QPILRFLQLL CENHNRDLQN FLRCQNNKTN YNLV CETLQ FLDCICGSTT GGLGLLGLYI NEKNVALINQ TLESLTEYCQ GPCHENQNCI ATHESNGIDI ITALILNDIN PLGKK RMDL VLELKNNASK LLLAIMESRH DSENAERILY NMRPKELVEV IKKAYMQGEV EFEDGENGED GAASPRNVGH NIYILA HQL ARHNKELQTM LKPGGQVDGD EALEFYAKHT AQIEIVRLDR TMEQIVFPVP SICEFLTKES KLRIYYTTER DEQGSKI ND FFLRSEDLFN EMNWQKKLRA QPVLYWCARN MSFWSSISFN LAVLMNLLVA FFYPFKGVRG GTLEPHWSGL LWTAMLIS L AIVIALPKPH GIRALIASTI LRLIFSVGLQ PTLFLLGAFN VCNKIIFLMS FVGNCGTFTR GYRAMVLDVE FLYHLLYLL ICAMGLFVHE FFYSLLLFDL VYREETLLNV IKSVTRNGRP IILTAALALI LVYLFSIVGY LFFKDDFILE VDRLPNETAG PETGESLAN DFLYSDVCRV ETGENCTSPA PKEELLPVEE TEQDKEHTCE TLLMCIVTVL SHGLRSGGGV GDVLRKPSKE E PLFAARVI YDLLFFFMVI IIVLNLIFGV IIDTFADLRS EKQKKEEILK TTCFICGLER DKFDNKTVTF EEHIKEEHNM WH YLCFIVL VKVKDSTEYT GPESYVAEMI RERNLDWFPR MRAMSLVSSD SEGEQNELRN LQEKLESTMK LVTNLSGQLS ELK DQMTEQ RKQKQRIGLL GHP

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Macromolecule #2: Adenophostin A

MacromoleculeName: Adenophostin A / type: ligand / ID: 2 / Number of copies: 4 / Formula: JYP
Molecular weightTheoretical: 669.322 Da
Chemical component information

ChemComp-JYP:
Adenophostin A

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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

Concentration0.1 mg/mL
BufferpH: 7.4
Details: 50 mM Tris-HCl buffer (pH 7.4), 150 mM NaCl, 1 mM DTT, 0.4% CHAPS,100 nM of AdA, 300 nM of Ca2+, protease inhibitors
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TECNAI F30
TemperatureMin: 93.0 K / Max: 93.0 K
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Frames/image: 2-17 / Number real images: 14686 / Average exposure time: 0.2 sec. / Average electron dose: 1.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.0 mm
Sample stageSpecimen holder model: GATAN 910 MULTI-SPECIMEN SINGLE TILT CRYO TRANSFER HOLDER
Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 191646
CTF correctionSoftware - Name: CTFFIND (ver. 3)
Startup modelType of model: EMDB MAP
EMDB ID:

6369

Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 1.4)
Details: Image processing was performed independently using RELION and EMAN2 to near-atomic resolution in large regions of the structure. Local resolution assessment performed independently for each ...Details: Image processing was performed independently using RELION and EMAN2 to near-atomic resolution in large regions of the structure. Local resolution assessment performed independently for each map revealed different domains were better resolved by each software package. To avoid human bias and extract the most information from each reconstruction the final map was a locally filtered average of the EMAN2 and RELION map. To combine the two maps, a local resolution filter, based on a windowed FSC local resolution assessment, was performed independently on the two maps. The two locally filtered maps were then averaged together. The local filtration determines the contribution of each map at each resolution in each region of the final composite map, permitting each map to dominate in regions where better self-consistency was obtained during refinement.
Number images used: 179760
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 1.4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 1.4)
Final 3D classificationNumber classes: 6 / Software - Name: RELION (ver. 1.4)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-6mu1:
Structure of full-length IP3R1 channel bound with Adenophostin A

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