+Open data
-Basic information
Entry | Database: PDB / ID: 7zub | ||||||||||||
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Title | Cryo-EM structure of the indirubin-bound Hsp90-XAP2-AHR complex | ||||||||||||
Components |
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Keywords | GENE 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 molecule of bacterial origin / regulation of adaptive immune response / receptor ligand inhibitor activity / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / nuclear aryl hydrocarbon receptor complex / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process ...GAF domain binding / cytosolic aryl hydrocarbon receptor complex / regulation of B cell proliferation / cellular response to molecule of bacterial origin / regulation of adaptive immune response / receptor ligand inhibitor activity / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / nuclear aryl hydrocarbon receptor complex / HSP90-CDC37 chaperone complex / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / negative regulation of T cell mediated immune response to tumor cell / dynein axonemal particle / histone methyltransferase binding / regulation of protein kinase A signaling / E-box binding / Xenobiotics / protein targeting to mitochondrion / positive regulation of protein localization to cell surface / ATP-dependent protein binding / Phase I - Functionalization of compounds / protein kinase regulator activity / protein folding chaperone complex / protein maturation by protein folding / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / Uptake and function of diphtheria toxin / TPR domain binding / blood vessel development / positive regulation of transforming growth factor beta receptor signaling pathway / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / : / aryl hydrocarbon receptor binding / TFIID-class transcription factor complex binding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / The NLRP3 inflammasome / telomere maintenance via telomerase / HSF1-dependent transactivation / response to unfolded protein / chaperone-mediated protein complex assembly / HSF1 activation / Attenuation phase / cellular response to interleukin-4 / Endogenous sterols / cis-regulatory region sequence-specific DNA binding / RHOBTB2 GTPase cycle / axonal growth cone / Purinergic signaling in leishmaniasis infection / DNA polymerase binding / supramolecular fiber organization / chaperone-mediated protein folding / cellular response to cAMP / cellular response to forskolin / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / protein folding chaperone / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / nitric-oxide synthase regulator activity / TBP-class protein binding / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / xenobiotic metabolic process / cAMP-mediated signaling / ESR-mediated signaling / peptide binding / peptidyl-prolyl cis-trans isomerase activity / placenta development / positive regulation of cell differentiation / ATP-dependent protein folding chaperone / kinase binding / PPARA activates gene expression / negative regulation of inflammatory response / circadian regulation of gene expression / Hsp90 protein binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / tau protein binding / response to toxic substance / Regulation of actin dynamics for phagocytic cup formation / transcription coactivator binding / nuclear receptor activity / histone deacetylase binding / Chaperone Mediated Autophagy / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / double-stranded RNA binding / sequence-specific double-stranded DNA binding / unfolded protein binding / melanosome / protein folding / MHC class II protein complex binding / regulation of gene expression / cellular response to heat / Potential therapeutics for SARS / transcription regulator complex / secretory granule lumen / Estrogen-dependent gene expression Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å | ||||||||||||
Authors | Gruszczyk, J. / Savva, C.G. / Lai-Kee-Him, J. / Bous, J. / Ancelin, A. / Kwong, H.S. / Grandvuillemin, L. / Bourguet, W. | ||||||||||||
Funding support | European Union, France, 3items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7zub.cif.gz | 674 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7zub.ent.gz | 555.2 KB | Display | PDB format |
PDBx/mmJSON format | 7zub.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7zub_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 7zub_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 7zub_validation.xml.gz | 59.1 KB | Display | |
Data in CIF | 7zub_validation.cif.gz | 89.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zu/7zub ftp://data.pdbj.org/pub/pdb/validation_reports/zu/7zub | HTTPS FTP |
-Related structure data
Related structure data | 14971MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 3 types, 4 molecules ABCD
#1: Protein | 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 | | 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 | | 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 | #5: Chemical | #6: Chemical | #7: Chemical | ChemComp-JY6 / ( | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Hsp90-XAP2-AHR complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT | |||||||||||||||||||||||||||||||||||
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Molecular weight | Value: 0.256 MDa / Experimental value: YES | |||||||||||||||||||||||||||||||||||
Source (natural) | Organism: Homo sapiens (human) | |||||||||||||||||||||||||||||||||||
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) | |||||||||||||||||||||||||||||||||||
Buffer solution | pH: 7 | |||||||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3 | |||||||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: 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 holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average 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 optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
-Processing
Software | Name: PHENIX / Version: 1.20_4459: / Classification: refinement | ||||||||||||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING ONLY | ||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 11546649 | ||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 678724 / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building |
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