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- PDB-7zub: Cryo-EM structure of the indirubin-bound Hsp90-XAP2-AHR complex -

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Basic information

Entry
Database: PDB / ID: 7zub
TitleCryo-EM structure of the indirubin-bound Hsp90-XAP2-AHR complex
Components
  • AH receptor-interacting protein
  • Aryl hydrocarbon receptor
  • Heat shock protein HSP 90-beta
KeywordsGENE REGULATION / complex / nuclear receptor / chemical pollutants / detoxification / cancer
Function / homology
Function and homology information


GAF domain binding / cytosolic aryl hydrocarbon receptor complex / regulation of B cell proliferation / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / regulation of adaptive immune response / HSP90-CDC37 chaperone complex / nuclear aryl hydrocarbon receptor complex / negative regulation of proteasomal protein catabolic process / cellular response to molecule of bacterial origin / Aryl hydrocarbon receptor signalling ...GAF domain binding / cytosolic aryl hydrocarbon receptor complex / regulation of B cell proliferation / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / regulation of adaptive immune response / HSP90-CDC37 chaperone complex / nuclear aryl hydrocarbon receptor complex / negative regulation of proteasomal protein catabolic process / cellular response to molecule of bacterial origin / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / negative regulation of T cell mediated immune response to tumor cell / protein kinase A signaling / dynein axonemal particle / histone methyltransferase binding / receptor ligand inhibitor activity / ATP-dependent protein binding / Xenobiotics / positive regulation of protein localization to cell surface / Phase I - Functionalization of compounds / protein kinase regulator activity / protein folding chaperone complex / protein targeting to mitochondrion / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / blood vessel development / positive regulation of transforming growth factor beta receptor signaling pathway / Uptake and function of diphtheria toxin / E-box binding / TPR domain binding / Assembly and release of respiratory syncytial virus (RSV) virions / aryl hydrocarbon receptor binding / TFIID-class transcription factor complex binding / dendritic growth cone / The NLRP3 inflammasome / protein phosphatase activator activity / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / Endogenous sterols / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / axonal growth cone / RHOBTB2 GTPase cycle / Purinergic signaling in leishmaniasis infection / cis-regulatory region sequence-specific DNA binding / supramolecular fiber organization / : / DNA polymerase binding / cellular response to cAMP / heat shock protein binding / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / TBP-class protein binding / nitric-oxide synthase regulator activity / cellular response to forskolin / protein folding chaperone / xenobiotic metabolic process / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / protein maturation / cellular response to interleukin-4 / peptide binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / ESR-mediated signaling / peptidyl-prolyl cis-trans isomerase activity / positive regulation of cell differentiation / placenta development / Hsp90 protein binding / circadian regulation of gene expression / ATP-dependent protein folding chaperone / transcription coactivator binding / PPARA activates gene expression / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Regulation of actin dynamics for phagocytic cup formation / tau protein binding / negative regulation of inflammatory response / kinase binding / histone deacetylase binding / response to toxic substance / nuclear receptor activity / Chaperone Mediated Autophagy / sequence-specific double-stranded DNA binding / disordered domain specific binding / MHC class II protein complex binding / The role of GTSE1 in G2/M progression after G2 checkpoint / positive regulation of nitric oxide biosynthetic process / unfolded protein binding / melanosome / protein folding / double-stranded RNA binding / regulation of protein localization / cellular response to heat / regulation of gene expression / secretory granule lumen / transcription regulator complex / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS
Similarity search - Function
: / AH receptor-interacting protein, N-terminal FKBP-type PPIase / Aryl hydrocarbon receptor / Aryl hydrocarbon receptor/Aryl hydrocarbon receptor repressor / AIP/AIPL1 / PAS fold-3 / PAS fold / Helix-loop-helix DNA-binding domain / Chitinase A; domain 3 - #40 / PAC motif ...: / AH receptor-interacting protein, N-terminal FKBP-type PPIase / Aryl hydrocarbon receptor / Aryl hydrocarbon receptor/Aryl hydrocarbon receptor repressor / AIP/AIPL1 / PAS fold-3 / PAS fold / Helix-loop-helix DNA-binding domain / Chitinase A; domain 3 - #40 / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / Tetratricopeptide repeat domain / Chitinase A; domain 3 / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / Peptidyl-prolyl cis-trans isomerase domain superfamily / TPR repeat region circular profile. / PAS fold / PAS fold / TPR repeat profile. / PAS domain / Tetratricopeptide repeat / PAS repeat profile. / PAS domain / PAS domain superfamily / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold / Roll / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Chem-JY6 / MOLYBDATE ION / AH receptor-interacting protein / Heat shock protein HSP 90-beta / Aryl hydrocarbon receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsGruszczyk, J. / Savva, C.G. / Lai-Kee-Him, J. / Bous, J. / Ancelin, A. / Kwong, H.S. / Grandvuillemin, L. / Bourguet, W.
Funding supportEuropean Union, France, 3items
OrganizationGrant numberCountry
European Union (EU)825489European Union
ATIP-AvenirR20059SP France
Montpellier University of Excellence (MUSE)ANR-16-IDEX-0006 France
CitationJournal: Nat Commun / Year: 2022
Title: Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex.
Authors: Jakub Gruszczyk / Loïc Grandvuillemin / Josephine Lai-Kee-Him / Matteo Paloni / Christos G Savva / Pierre Germain / Marina Grimaldi / Abdelhay Boulahtouf / Hok-Sau Kwong / Julien Bous / ...Authors: Jakub Gruszczyk / Loïc Grandvuillemin / Josephine Lai-Kee-Him / Matteo Paloni / Christos G Savva / Pierre Germain / Marina Grimaldi / Abdelhay Boulahtouf / Hok-Sau Kwong / Julien Bous / Aurélie Ancelin / Cherine Bechara / Alessandro Barducci / Patrick Balaguer / William Bourguet /
Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including ...The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including pollutants, natural products and metabolites. However, the scarcity of structural data precludes understanding of how AHR is activated by such diverse compounds. Our 2.85 Å structure of the human indirubin-bound AHR complex with the chaperone Hsp90 and the co-chaperone XAP2, reported herein, reveals a closed conformation Hsp90 dimer with AHR threaded through its lumen and XAP2 serving as a brace. Importantly, we disclose the long-awaited structure of the AHR PAS-B domain revealing a unique organisation of the ligand-binding pocket and the structural determinants of ligand-binding specificity and promiscuity of the receptor. By providing structural details of the molecular initiating event leading to AHR activation, our study rationalises almost forty years of biochemical data and provides a framework for future mechanistic studies and structure-guided drug design.
History
DepositionMay 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Data collection / Database references
Category: citation / citation_author / pdbx_initial_refinement_model
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 7, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jul 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-beta
B: Heat shock protein HSP 90-beta
C: AH receptor-interacting protein
D: Aryl hydrocarbon receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)257,37011
Polymers255,8854
Non-polymers1,4857
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area20110 Å2
ΔGint-154 kcal/mol
Surface area79510 Å2
MethodPISA

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Components

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Protein , 3 types, 4 molecules ABCD

#1: Protein Heat shock protein HSP 90-beta / HSP 90 / Heat shock 84 kDa / HSP 84 / HSP84


Mass: 84213.141 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AB1, HSP90B, HSPC2, HSPCB / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08238
#2: Protein AH receptor-interacting protein / AIP / Aryl-hydrocarbon receptor-interacting protein / HBV X-associated protein 2 / XAP-2 / ...AIP / Aryl-hydrocarbon receptor-interacting protein / HBV X-associated protein 2 / XAP-2 / Immunophilin homolog ARA9


Mass: 37691.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AIP, XAP2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O00170
#3: Protein Aryl hydrocarbon receptor / Ah receptor / AhR / Class E basic helix-loop-helix protein 76 / bHLHe76


Mass: 49767.879 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AHR, BHLHE76 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35869

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Non-polymers , 4 types, 7 molecules

#4: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-MOO / MOLYBDATE ION / MOLYBDATE


Mass: 159.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: MoO4
#7: Chemical ChemComp-JY6 / (3~{Z})-3-(3-oxidanylidene-1~{H}-indol-2-ylidene)-1~{H}-indol-2-one / indirubin


Mass: 262.263 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H10N2O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: Hsp90-XAP2-AHR complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.256 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMbis-tris methaneBis-Tris1
250 mMsodium chlorideNaCl1
310 mMpotassium chlorideKCl1
410 mMmagnesium chlorideMgCl21
520 mMsodium molybdateNa2MoO41
62 mM2-mercaptoethanolBME1
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3 sec. / Electron dose: 1.1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9300
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
EM software
IDNameVersionCategory
1RELION3.1.1particle selection
2EPUimage acquisition
4RELION3.1.1CTF correction
7UCSF ChimeraX1.3model fitting
8Coot0.8.9.2model fitting
10RELION3.1.1initial Euler assignment
11RELION3.1.1final Euler assignment
12RELION3.1.1classification
13RELION3.1.13D reconstruction
14PHENIX1.2model refinement
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 11546649
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 678724 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
15FWP

5fwp

15FWP1PDBexperimental model
24F3L

4f3l

14F3L2PDBexperimental model
34ZPR

4zpr

14ZPR3PDBexperimental model
42LKN

2lkn

12LKN4PDBexperimental model
54AIF

4aif

14AIF5PDBexperimental model

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