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

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Basic information

Entry
Database: PDB / ID: 6mu1
TitleStructure of full-length IP3R1 channel bound with Adenophostin A
ComponentsInositol 1,4,5-trisphosphate receptor type 1
KeywordsMEMBRANE PROTEIN / inositol 1 / 4 / 5-trisphosphate receptor / calcium release channel / neuronal type 1 / adenophostin A / IP3R-channel activator
Function / homology
Function and homology information


ion channel regulator activity involved in G protein-coupled receptor signaling pathway / Effects of PIP2 hydrolysis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / channel activator activity / 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 tubular network / platelet dense granule membrane ...ion channel regulator activity involved in G protein-coupled receptor signaling pathway / Effects of PIP2 hydrolysis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / channel activator activity / 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 tubular network / platelet dense granule membrane / negative regulation of calcium-mediated signaling / inositol phosphate-mediated signaling / inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / calcineurin complex / epithelial fluid transport / phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / 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 / nuclear inner membrane / transport vesicle membrane / calcium channel regulator activity / Ion homeostasis / calcium-release channel activity / dendrite development / ligand-gated ion channel signaling pathway / ion channel modulating, G protein-coupled receptor signaling pathway / GABA-ergic synapse / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / release of sequestered calcium ion into cytosol / calcium channel inhibitor activity / phosphatidylinositol binding / liver regeneration / post-embryonic development / secretory granule membrane / sarcoplasmic reticulum / synaptic membrane / cellular response to cAMP / positive regulation of neuron projection development / Schaffer collateral - CA1 synapse / calcium-mediated signaling / negative regulation of neuron death / positive regulation of insulin secretion / cell morphogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / calcium ion transport / presynapse / nuclear envelope / cellular response to hypoxia / postsynapse / positive regulation of cytosolic calcium ion concentration / transmembrane transporter binding / protein phosphatase binding / response to hypoxia / postsynaptic density / positive regulation of apoptotic process / protein domain specific binding / membrane raft / intracellular membrane-bounded organelle / synapse / neuronal cell body / dendrite / protein-containing complex binding / endoplasmic reticulum membrane / nucleolus / 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 ...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
Adenophostin A / Inositol 1,4,5-trisphosphate receptor type 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsSerysheva, I.I. / Fan, G. / Baker, M.R. / Wang, Z. / Seryshev, A. / Ludtke, S.J. / Baker, M.L.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM072804 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R21NS106968 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 General Medical Sciences (NIH/NIGMS)R01GM080139 United States
American Heart Association16GRNT2972000 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, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)1,252,4458
Polymers1,249,7684
Non-polymers2,6774
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Inositol 1,4,5-trisphosphate receptor type 1 / IP3 receptor isoform 1 / InsP3R1 / Type 1 inositol 1 / 4 / 5-trisphosphate receptor / Type 1 InsP3 receptor


Mass: 312442.000 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Rattus norvegicus (Norway rat) / References: UniProt: P29994
#2: Chemical
ChemComp-JYP / Adenophostin A / [(2~{R},3~{R},4~{S},5~{R})-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)-4-[(2~{R},3~{S},4~{R},5~{S},6~{S})-6-(hydroxymethyl)-3-oxidanyl-4,5-diphosphonooxy-oxan-2-yl]oxy-oxolan-3-yl] dihydrogen phosphate


Mass: 669.322 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H26N5O18P3

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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: COMPLEX / Details: tetrameric assembly / Entity ID: #1 / Source: NATURAL
Molecular weightValue: 1.3 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat) / Cellular location: membrane / Organ: Brain / Organelle: endoplasmic reticulum / Tissue: Cerebellum
Buffer solutionpH: 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
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K

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Electron microscopy imaging

Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F30
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2 mm
Specimen holderCryogen: NITROGEN
Specimen holder model: GATAN 910 MULTI-SPECIMEN SINGLE TILT CRYO TRANSFER HOLDER
Temperature (max): 93 K / Temperature (min): 93 K
Image recordingAverage exposure time: 0.2 sec. / Electron dose: 1.3 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 14686
Image scansMovie frames/image: 35 / Used frames/image: 2-17

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Processing

EM software
IDNameVersionCategoryDetails
2SerialEMimage acquisition
4CTFFIND3CTF correction
7Cootmodel fitting
9RELION1.4initial Euler assignment
10RELION1.4final Euler assignment
11RELION1.4classification
12RELION1.43D reconstruction
13PHENIXmodel refinementreal space refine
14Gorgonmodel fitting
15Pathwalkingmodel fitting
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 191646
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 179760
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.
Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL

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