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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-betaHeat shock response
KeywordsGENE REGULATION / complex / nuclear receptor / chemical pollutants / detoxification / cancer
Function / homology
Function and homology information


GAF domain binding / negative regulation of T cell mediated immune response to tumor cell / cytosolic aryl hydrocarbon receptor complex / regulation of B cell proliferation / cellular response to molecule of bacterial origin / regulation of adaptive immune response / : / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / nuclear aryl hydrocarbon receptor complex / HSP90-CDC37 chaperone complex ...GAF domain binding / negative regulation of T cell mediated immune response to tumor cell / cytosolic aryl hydrocarbon receptor complex / regulation of B cell proliferation / cellular response to molecule of bacterial origin / regulation of adaptive immune response / : / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / nuclear aryl hydrocarbon receptor complex / HSP90-CDC37 chaperone complex / positive regulation of cyclin-dependent protein kinase activity / Aryl hydrocarbon receptor signalling / negative regulation of proteasomal protein catabolic process / dynein axonemal particle / aryl hydrocarbon receptor complex / histone methyltransferase binding / regulation of protein kinase A signaling / protein kinase regulator activity / positive regulation of protein localization to cell surface / protein targeting to mitochondrion / Xenobiotics / ATP-dependent protein binding / Phase I - Functionalization of compounds / negative regulation of protein metabolic process / protein maturation by protein folding / positive regulation of tau-protein kinase activity / telomerase holoenzyme complex assembly / Uptake and function of diphtheria toxin / blood vessel development / TPR domain binding / E-box binding / positive regulation of transforming growth factor beta receptor signaling pathway / dendritic growth cone / TFIID-class transcription factor complex binding / positive regulation of phosphoprotein phosphatase activity / aryl hydrocarbon receptor binding / cAMP-mediated signaling / Sema3A PAK dependent Axon repulsion / The NLRP3 inflammasome / regulation of protein ubiquitination / HSF1-dependent transactivation / telomere maintenance via telomerase / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / response to unfolded protein / HSF1 activation / chaperone-mediated protein complex assembly / Attenuation phase / Endogenous sterols / RHOBTB2 GTPase cycle / cis-regulatory region sequence-specific DNA binding / DNA polymerase binding / Purinergic signaling in leishmaniasis infection / supramolecular fiber organization / axonal growth cone / cellular response to forskolin / cellular response to cAMP / positive regulation of telomerase activity / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / TBP-class protein binding / cellular response to interleukin-4 / xenobiotic metabolic process / nitric-oxide synthase regulator activity / ESR-mediated signaling / placenta development / peptidyl-prolyl cis-trans isomerase activity / positive regulation of cell differentiation / peptide binding / ATP-dependent protein folding chaperone / Hsp90 protein binding / tau protein binding / circadian regulation of gene expression / DDX58/IFIH1-mediated induction of interferon-alpha/beta / transcription coactivator binding / PPARA activates gene expression / response to toxic substance / Regulation of actin dynamics for phagocytic cup formation / negative regulation of inflammatory response / kinase binding / Chaperone Mediated Autophagy / histone deacetylase binding / The role of GTSE1 in G2/M progression after G2 checkpoint / nuclear receptor activity / positive regulation of nitric oxide biosynthetic process / regulation of protein localization / disordered domain specific binding / melanosome / unfolded protein binding / sequence-specific double-stranded DNA binding / double-stranded RNA binding / protein folding / cellular response to heat / MHC class II protein complex binding / regulation of gene expression / secretory granule lumen / Estrogen-dependent gene expression / ficolin-1-rich granule lumen / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding
Similarity search - Function
Aryl hydrocarbon receptor / Aryl hydrocarbon receptor/Aryl hydrocarbon receptor repressor / AIP/AIPL1 / PAS fold-3 / PAS fold / Helix-loop-helix DNA-binding domain / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. ...Aryl hydrocarbon receptor / Aryl hydrocarbon receptor/Aryl hydrocarbon receptor repressor / AIP/AIPL1 / PAS fold-3 / PAS fold / Helix-loop-helix DNA-binding domain / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / 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 / FKBP-type peptidyl-prolyl cis-trans isomerase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Peptidyl-prolyl cis-trans isomerase domain superfamily / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / TPR repeat region circular profile. / TPR repeat profile. / PAS fold / PAS fold / 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 / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold
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

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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
Water0
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 / Heat shock response / 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 / Adenosine 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 / 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 / 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-TrisBis-tris methane1
250 mMsodium chlorideNaClSodium chloride1
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 FIELDBright-field microscopy / 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-ID
15FWP

5fwp

1
24F3L

4f3l

1
34ZPR

4zpr

1
42LKN

2lkn

1
54AIF

4aif

1

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