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- PDB-9i3f: Crystal structure of the AGR2 and IRE1beta_loop complex -

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Basic information

Entry
Database: PDB / ID: 9i3f
TitleCrystal structure of the AGR2 and IRE1beta_loop complex
Components
  • Anterior gradient protein 2 homolog
  • Serine/threonine-protein kinase/endoribonuclease IRE2
KeywordsCHAPERONE / molecular chaperones / unfolded protein response (UPR) / endoplasmic reticulum (ER) / protein multimerisation
Function / homology
Function and homology information


lung goblet cell differentiation / positive regulation of PERK-mediated unfolded protein response / apoptotic chromosome condensation / IRE1-TRAF2-ASK1 complex / endoplasmic reticulum quality control compartment / mucus secretion / dystroglycan binding / rRNA catabolic process / positive regulation of developmental growth / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters ...lung goblet cell differentiation / positive regulation of PERK-mediated unfolded protein response / apoptotic chromosome condensation / IRE1-TRAF2-ASK1 complex / endoplasmic reticulum quality control compartment / mucus secretion / dystroglycan binding / rRNA catabolic process / positive regulation of developmental growth / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / positive regulation of cell-substrate adhesion / epidermal growth factor receptor binding / positive regulation of epidermal growth factor receptor signaling pathway / IRE1-mediated unfolded protein response / digestive tract morphogenesis / positive regulation of IRE1-mediated unfolded protein response / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / RNA endonuclease activity / response to endoplasmic reticulum stress / positive regulation of protein localization to plasma membrane / mRNA processing / unfolded protein binding / endonuclease activity / protein phosphorylation / non-specific serine/threonine protein kinase / inflammatory response / protein serine kinase activity / negative regulation of DNA-templated transcription / protein serine/threonine kinase activity / positive regulation of gene expression / magnesium ion binding / endoplasmic reticulum / extracellular space / extracellular region / ATP binding / identical protein binding / cytosol
Similarity search - Function
: / Thioredoxin-like / Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat ...: / Thioredoxin-like / Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / Quinoprotein alcohol dehydrogenase-like superfamily / Thioredoxin-like superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Anterior gradient protein 2 homolog / Serine/threonine-protein kinase/endoribonuclease IRE2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsYan, Y. / Ron, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome TrustSGAG/182 United Kingdom
CitationJournal: Mol Cell / Year: 2025
Title: A structural basis for chaperone repression of stress signaling from the endoplasmic reticulum.
Authors: Lisa Neidhardt / Joanne Tung / Miriam Kuchersky / Jakub Milczarek / Vasileios Kargas / Katherine Stott / Rina Rosenzweig / David Ron / Yahui Yan /
Abstract: The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. Reserve chaperones suppress UPR transducers via their stress-sensing ...The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. Reserve chaperones suppress UPR transducers via their stress-sensing luminal domains, but the underlying mechanisms remain unclear. The ER chaperone AGR2 is known to repress the UPR transducer IRE1β. Here, structural prediction, X-ray crystallography, and NMR spectroscopy identify critical interactions between an AGR2 monomer and a regulatory loop in IRE1β's luminal domain. However, in the repressive complex, it is an AGR2 dimer that binds IRE1β. Cryoelectron microscopy (cryo-EM) reconstruction explains this feature: one AGR2 protomer engages the regulatory loop, while the second asymmetrically binds IRE1β's luminal domain's C terminus, blocking IRE1β-activating dimerization. Molecular dynamic simulations indicate that the second, disruptive AGR2 protomer exploits rare fluctuations in the IRE1β dimer that expose its binding site. Thus, AGR2 disrupts IRE1β dimers to suppress the UPR, priming the system for activation by chaperone clients that compete for AGR2.
History
DepositionJan 22, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 29, 2025Group: Database references / Category: citation
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Nov 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Nov 19, 2025Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
I: Serine/threonine-protein kinase/endoribonuclease IRE2
A: Anterior gradient protein 2 homolog
B: Anterior gradient protein 2 homolog
C: Anterior gradient protein 2 homolog
D: Anterior gradient protein 2 homolog
F: Serine/threonine-protein kinase/endoribonuclease IRE2
G: Serine/threonine-protein kinase/endoribonuclease IRE2
H: Serine/threonine-protein kinase/endoribonuclease IRE2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,81911
Polymers82,7468
Non-polymers733
Water6,648369
1
I: Serine/threonine-protein kinase/endoribonuclease IRE2
B: Anterior gradient protein 2 homolog
D: Anterior gradient protein 2 homolog
F: Serine/threonine-protein kinase/endoribonuclease IRE2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3975
Polymers41,3734
Non-polymers241
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Anterior gradient protein 2 homolog
C: Anterior gradient protein 2 homolog
G: Serine/threonine-protein kinase/endoribonuclease IRE2
H: Serine/threonine-protein kinase/endoribonuclease IRE2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,4226
Polymers41,3734
Non-polymers492
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.199, 81.820, 120.871
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Serine/threonine-protein kinase/endoribonuclease IRE2 / Endoplasmic reticulum-to-nucleus signaling 2 / Inositol-requiring protein 2 / hIRE2p / Ire1-beta / IRE1b


Mass: 5544.084 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERN2, IRE2 / Production host: Escherichia (bacteria)
References: UniProt: Q76MJ5, non-specific serine/threonine protein kinase, Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters
#2: Protein
Anterior gradient protein 2 homolog / AG-2 / hAG-2 / HPC8 / Secreted cement gland protein XAG-2 homolog


Mass: 15142.388 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AGR2, AG2, UNQ515/PRO1030 / Production host: Escherichia (bacteria) / References: UniProt: O95994
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 369 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.76 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 0.2M Magnesium chloride, 0.1M TRIS PH8.5 and 24% PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 16, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.9→67.76 Å / Num. obs: 57731 / % possible obs: 99.6 % / Redundancy: 6.4 % / CC1/2: 0.992 / Rmerge(I) obs: 0.198 / Net I/σ(I): 6
Reflection shellResolution: 1.9→1.94 Å / Rmerge(I) obs: 1.234 / Num. unique obs: 17355 / CC1/2: 0.707

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Processing

Software
NameVersionClassification
REFMAC5.8.0430refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→67.76 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.924 / SU B: 4.957 / SU ML: 0.13 / Cross valid method: THROUGHOUT / ESU R: 0.151 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2341 2862 5 %RANDOM
Rwork0.19948 ---
obs0.20116 54791 99.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.997 Å2
Baniso -1Baniso -2Baniso -3
1--1.86 Å2-0 Å20 Å2
2--3.72 Å2-0 Å2
3----1.85 Å2
Refinement stepCycle: 1 / Resolution: 1.9→67.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4789 0 3 369 5161
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0124939
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164751
X-RAY DIFFRACTIONr_angle_refined_deg1.2461.8456714
X-RAY DIFFRACTIONr_angle_other_deg0.4541.77210974
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7415597
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.928523
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.42310885
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0610.2776
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.025644
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021052
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2892.0712403
X-RAY DIFFRACTIONr_mcbond_other1.2892.0712403
X-RAY DIFFRACTIONr_mcangle_it2.1783.7012995
X-RAY DIFFRACTIONr_mcangle_other2.1783.7012996
X-RAY DIFFRACTIONr_scbond_it1.7432.2492536
X-RAY DIFFRACTIONr_scbond_other1.7432.2492537
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.914.0443720
X-RAY DIFFRACTIONr_long_range_B_refined4.24921.625470
X-RAY DIFFRACTIONr_long_range_B_other4.17520.795393
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.34 214 -
Rwork0.361 3785 -
obs--94.49 %

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