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- EMDB-14972: Cryo-EM structure of the indirubin-bound Hsp90-XAP2-AHR complex (... -

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Basic information

Entry
Database: EMDB / ID: EMD-14972
TitleCryo-EM structure of the indirubin-bound Hsp90-XAP2-AHR complex (focused map).
Map data
Sample
  • Complex: Hsp90-XAP2-AHR complex
Keywordscomplex / nuclear receptor / chemical pollutants / detoxification / cancer / GENE REGULATION
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.07 Å
AuthorsGruszczyk J / Savva CG / Lai-Kee-Him J / Bous J / Ancelin A / Kwong HS / Grandvuillemin L / Bourguet W
Funding supportEuropean Union, France, 3 items
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, 2022-
Header (metadata) releaseNov 23, 2022-
Map releaseNov 23, 2022-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14972.png

Downloads & links

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Map

FileDownload / File: emd_14972.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.086 Å
Density
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.07112698 - 0.119602785
Average (Standard dev.)0.00019310744 (±0.0028376195)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 195.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_14972_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_14972_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_14972_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Hsp90-XAP2-AHR complex

EntireName: Hsp90-XAP2-AHR complex
Components
  • Complex: Hsp90-XAP2-AHR complex

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Supramolecule #1: Hsp90-XAP2-AHR complex

SupramoleculeName: Hsp90-XAP2-AHR complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 256 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
20.0 mMBis-Trisbis-tris methane
50.0 mMNaClsodium chloride
10.0 mMKClpotassium chloride
10.0 mMMgCl2magnesium chloride
20.0 mMNa2MoO4sodium molybdate
2.0 mMBME2-mercaptoethanol
GridModel: C-flat-1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 20 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 10 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9300 / Average exposure time: 3.0 sec. / Average electron dose: 1.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 11546649
Startup modelType of model: INSILICO MODEL / In silico model: Ab initio model generated with RELION
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.07 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1) / Number images used: 116399
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1.1)
Final 3D classificationNumber classes: 1 / Avg.num./class: 116399 / Software - Name: RELION (ver. 3.1.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5fwp

source_name: PDB, initial_model_type: experimental model

4f3l

source_name: PDB, initial_model_type: experimental model

4zpr

source_name: PDB, initial_model_type: experimental model

2lkn

source_name: PDB, initial_model_type: experimental model

4aif

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT

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