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- PDB-8qmo: Cryo-EM structure of the benzo[a]pyrene-bound Hsp90-XAP2-AHR complex -

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Basic information

Entry
Database: PDB / ID: 8qmo
TitleCryo-EM structure of the benzo[a]pyrene-bound Hsp90-XAP2-AHR complex
Components
  • AH receptor-interacting protein
  • Aryl hydrocarbon receptor
  • Heat shock protein HSP 90-beta
KeywordsTRANSCRIPTION / detoxification / chemical pollutants / exposome
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 / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) ...: / 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 / 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 / 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 / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / MOLYBDATE ION / benzo[a]pyrene / 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: 2.76 Å
AuthorsKwong, H.S. / Grandvuillemin, L. / Sirounian, S. / Ancelin, A. / Lai-Kee-Him, J. / Carivenc, C. / Lancey, C. / Ragan, T.J. / Hesketh, E.L. / Bourguet, W. / Gruszczyk, J.
Funding support France, 4items
OrganizationGrant numberCountry
ATIP-AvenirR20059SP France
Montpellier University of Excellence (MUSE)ANR-16-IDEX-0006 France
Other governmentEXPOAR23-RS03-JakubGruszczy
French National Research AgencyANR-10-INBS-04-01 France
CitationJournal: J Mol Biol / Year: 2024
Title: Structural Insights into the Activation of Human Aryl Hydrocarbon Receptor by the Environmental Contaminant Benzo[a]pyrene and Structurally Related Compounds.
Authors: Hok-Sau Kwong / Matteo Paloni / Loïc Grandvuillemin / Savannah Sirounian / Aurélie Ancelin / Josephine Lai-Kee-Him / Marina Grimaldi / Coralie Carivenc / Claudia Lancey / Timothy J Ragan / ...Authors: Hok-Sau Kwong / Matteo Paloni / Loïc Grandvuillemin / Savannah Sirounian / Aurélie Ancelin / Josephine Lai-Kee-Him / Marina Grimaldi / Coralie Carivenc / Claudia Lancey / Timothy J Ragan / Emma L Hesketh / Patrick Balaguer / Alessandro Barducci / Jakub Gruszczyk / William Bourguet /
Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor belonging to the bHLH/PAS protein family and responding to hundreds of natural and chemical substances. It is primarily ...The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor belonging to the bHLH/PAS protein family and responding to hundreds of natural and chemical substances. It is primarily involved in the defense against chemical insults and bacterial infections or in the adaptive immune response, but also in the development of pathological conditions ranging from inflammatory to neoplastic disorders. Despite its prominent roles in many (patho)physiological processes, the lack of high-resolution structural data has precluded for thirty years an in-depth understanding of the structural mechanisms underlying ligand-binding specificity, promiscuity and activation of AHR. We recently reported a cryogenic electron microscopy (cryo-EM) structure of human AHR bound to the natural ligand indirubin, the chaperone Hsp90 and the co-chaperone XAP2 that provided the first experimental visualization of its ligand-binding PAS-B domain. Here, we report a 2.75 Å resolution structure of the AHR complex bound to the environmental pollutant benzo[a]pyrene (B[a]P). The structure substantiates the existence of a bipartite PAS-B ligand-binding pocket with a geometrically constrained primary binding site controlling ligand binding specificity and affinity, and a secondary binding site contributing to the binding promiscuity of AHR. We also report a docking study of B[a]P congeners that validates the B[a]P-bound PAS-B structure as a suitable model for accurate computational ligand binding assessment. Finally, comparison of our agonist-bound complex with the recently reported structures of mouse and fruit fly AHR PAS-B in different activation states suggests a ligand-induced loop conformational change potentially involved in the regulation of AHR function.
History
DepositionSep 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 10, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.title / _citation.year

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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)257,08511
Polymers255,6104
Non-polymers1,4757
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable, gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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


Mass: 49492.559 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35869

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Non-polymers , 4 types, 7 molecules

#4: Chemical ChemComp-MOO / MOLYBDATE ION / MOLYBDATE


Mass: 159.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: MoO4
#5: 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
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#7: Chemical ChemComp-W62 / benzo[a]pyrene


Mass: 252.309 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H12 / 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: Benzo[a]pyrene-bound Hsp90-XAP2-AHR complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.254 MDa / Experimental value: NO
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.: 0.18 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: 298 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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2300 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 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: 9849

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Processing

EM software
IDNameVersionCategory
1RELION3.1.1particle selection
2EPUimage acquisition
4RELION3.1.1CTF correction
7UCSF ChimeraX1.6.1model fitting
9RELION3.1.1initial Euler assignment
10RELION3.1.1final Euler assignment
11RELION3.1.1classification
12RELION3.1.13D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 6327916
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 630113 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 7ZUB

7zub


Accession code: 7ZUB / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00814246
ELECTRON MICROSCOPYf_angle_d0.61419195
ELECTRON MICROSCOPYf_dihedral_angle_d4.1291930
ELECTRON MICROSCOPYf_chiral_restr0.0382117
ELECTRON MICROSCOPYf_plane_restr0.0042489

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