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Yorodumi- EMDB-18498: Cryo-EM structure of the benzo[a]pyrene-bound Hsp90-XAP2-AHR complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-18498 | |||||||||||||||
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Title | Cryo-EM structure of the benzo[a]pyrene-bound Hsp90-XAP2-AHR complex | |||||||||||||||
Map data | ||||||||||||||||
Sample |
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Keywords | detoxification / chemical pollutants / exposome / TRANSCRIPTION | |||||||||||||||
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 / negative regulation of proteasomal protein catabolic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / dynein axonemal particle / histone methyltransferase binding / regulation of protein kinase A signaling / protein targeting to mitochondrion / positive regulation of protein localization to cell surface / Xenobiotics / ATP-dependent protein binding / protein kinase regulator activity / Phase I - Functionalization of compounds / protein maturation by protein folding / negative regulation of protein metabolic process / positive regulation of tau-protein kinase activity / telomerase holoenzyme complex assembly / Uptake and function of diphtheria toxin / TPR domain binding / blood vessel development / 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 / Sema3A PAK dependent Axon repulsion / The NLRP3 inflammasome / regulation of protein ubiquitination / HSF1-dependent transactivation / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / telomere maintenance via telomerase / 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 / Purinergic signaling in leishmaniasis infection / axonal growth cone / supramolecular fiber organization / DNA polymerase binding / cellular response to cAMP / cellular response to forskolin / positive regulation of telomerase activity / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / TBP-class protein binding / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / nitric-oxide synthase regulator activity / cAMP-mediated signaling / xenobiotic metabolic process / ESR-mediated signaling / peptidyl-prolyl cis-trans isomerase activity / placenta development / positive regulation of cell differentiation / ATP-dependent protein folding chaperone / peptide binding / Hsp90 protein binding / circadian regulation of gene expression / DDX58/IFIH1-mediated induction of interferon-alpha/beta / tau protein binding / PPARA activates gene expression / response to toxic substance / Regulation of actin dynamics for phagocytic cup formation / kinase binding / transcription coactivator binding / histone deacetylase binding / negative regulation of inflammatory response / Chaperone Mediated Autophagy / The role of GTSE1 in G2/M progression after G2 checkpoint / nuclear receptor activity / regulation of protein localization / positive regulation of nitric oxide biosynthetic process / double-stranded RNA binding / disordered domain specific binding / unfolded protein binding / sequence-specific double-stranded DNA binding / melanosome / protein folding / MHC class II protein complex binding / cellular response to heat / regulation of gene expression / secretory granule lumen / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / ficolin-1-rich granule lumen / transcription regulator complex Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.76 Å | |||||||||||||||
Authors | Kwong HS / Grandvuillemin L / Sirounian S / Ancelin A / Lai-Kee-Him J / Carivenc C / Lancey C / Ragan TJ / Hesketh EL / Bourguet W / Gruszczyk J | |||||||||||||||
Funding support | France, 4 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_18498.map.gz | 13.6 MB | EMDB map data format | |
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Header (meta data) | emd-18498-v30.xml emd-18498.xml | 24.9 KB 24.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_18498_fsc.xml | 12.8 KB | Display | FSC data file |
Images | emd_18498.png | 86.4 KB | ||
Masks | emd_18498_msk_1.map | 178 MB | Mask map | |
Filedesc metadata | emd-18498.cif.gz | 7.7 KB | ||
Others | emd_18498_half_map_1.map.gz emd_18498_half_map_2.map.gz | 140.8 MB 140.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-18498 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-18498 | HTTPS FTP |
-Related structure data
Related structure data | 8qmoMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_18498.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_18498_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_18498_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_18498_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Benzo[a]pyrene-bound Hsp90-XAP2-AHR complex
Entire | Name: Benzo[a]pyrene-bound Hsp90-XAP2-AHR complex |
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Components |
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-Supramolecule #1: Benzo[a]pyrene-bound Hsp90-XAP2-AHR complex
Supramolecule | Name: Benzo[a]pyrene-bound Hsp90-XAP2-AHR complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 254 KDa |
-Macromolecule #1: Heat shock protein HSP 90-beta
Macromolecule | Name: Heat shock protein HSP 90-beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 84.213141 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHPEE VHHGEEEVET FAFQAEIAQL MSLIINTFYS NKEIFLRELI SNASDALDKI RYESLTDPSK LDSGKELKID IIPNPQERT LTLVDTGIGM TKADLINNLG TIAKSGTKAF MEALQAGADI SMIGQFGVGF YSAYLVAEKV VVITKHNDDE Q YAWESSAG ...String: MHHHHHHPEE VHHGEEEVET FAFQAEIAQL MSLIINTFYS NKEIFLRELI SNASDALDKI RYESLTDPSK LDSGKELKID IIPNPQERT LTLVDTGIGM TKADLINNLG TIAKSGTKAF MEALQAGADI SMIGQFGVGF YSAYLVAEKV VVITKHNDDE Q YAWESSAG GSFTVRADHG EPIGRGTKVI LHLKEDQTEY LEERRVKEVV KKHSQFIGYP ITLYLEKERE KEISDDEAEE EK GEKEEED KDDEEKPKIE DVGSDEEDDS GKDKKKKTKK IKEKYIDQEE LNKTKPIWTR NPDDITQEEY GEFYKSLTND WED HLAVKH FSVEGQLEFR ALLFIPRRAP FDLFENKKKK NNIKLYVRRV FIMDSCDELI PEYLNFIRGV VDSEDLPLNI SREM LQQSK ILKVIRKNIV KKCLELFSEL AEDKENYKKF YEAFSKNLKL GIHEDSTNRR RLSELLRYHT SQSGDEMTSL SEYVS RMKE TQKSIYYITG ESKEQVANSA FVERVRKRGF EVVYMTEPID EYCVQQLKEF DGKSLVSVTK EGLELPEDEE EKKKME ESK AKFENLCKLM KEILDKKVEK VTISNRLVSS PCCIVTSTYG WTANMERIMK AQALRDNSTM GYMMAKKHLE INPDHPI VE TLRQKAEADK NDKAVKDLVV LLFETALLSS GFSLEDPQTH SNRIYRMIKL GLGIDEDEVA AEEPNAAVPD EIPPLEGD E DASRMEEVD UniProtKB: Heat shock protein HSP 90-beta |
-Macromolecule #2: AH receptor-interacting protein
Macromolecule | Name: AH receptor-interacting protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 37.691047 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MADIIARLRE DGIQKRVIQE GRGELPDFQD GTKATFHYRT LHSDDEGTVL DDSRARGKPM ELIIGKKFKL PVWETIVCTM REGEIAQFL CDIKHVVLYP LVAKSLRNIA VGKDPLEGQR HCCGVAQMRE HSSLGHADLD ALQQNPQPLI FHMEMLKVES P GTYQQDPW ...String: MADIIARLRE DGIQKRVIQE GRGELPDFQD GTKATFHYRT LHSDDEGTVL DDSRARGKPM ELIIGKKFKL PVWETIVCTM REGEIAQFL CDIKHVVLYP LVAKSLRNIA VGKDPLEGQR HCCGVAQMRE HSSLGHADLD ALQQNPQPLI FHMEMLKVES P GTYQQDPW AMTDEEKAKA VPLIHQEGNR LYREGHVKEA AAKYYDAIAC LKNLQMKEQP GSPEWIQLDQ QITPLLLNYC QC KLVVEEY YEVLDHCSSI LNKYDDNVKA YFKRGKAHAA VWNAQEAQAD FAKVLELDPA LAPVVSRELQ ALEARIRQKD EED KARFRG IFSH UniProtKB: AH receptor-interacting protein |
-Macromolecule #3: Aryl hydrocarbon receptor
Macromolecule | Name: Aryl hydrocarbon receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 49.492559 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: GAPNSSSANI TYASRKRRKP VQKTVKPIPA EGIKSNPSKR HRDRLNTELD RLASLLPFPQ DVINKLDKLS VLRLSVSYLR AKSFFDVAL KSSPTERNGG QDNCRAANFR EGLNLQEGEF LLQALNGFVL VVTTDALVFY ASSTIQDYLG FQQSDVIHQS V YELIHTED ...String: GAPNSSSANI TYASRKRRKP VQKTVKPIPA EGIKSNPSKR HRDRLNTELD RLASLLPFPQ DVINKLDKLS VLRLSVSYLR AKSFFDVAL KSSPTERNGG QDNCRAANFR EGLNLQEGEF LLQALNGFVL VVTTDALVFY ASSTIQDYLG FQQSDVIHQS V YELIHTED RAEFQRQLHW ALNPSQCTES GQGIEEATGL PQTVVCYNPD QIPPENSPLM ERCFICRLRC LLDNSSGFLA MN FQGKLKY LHGQKKKGKD GSILPPQLAL FAIATPLQPP SILEIRTKNF IFRTKHKLDF TPIGCDAKGR IVLGYTEAEL CTR GSGYQF IHAADMLYCA ESHIRMIKTG ESGMIVFRLL TKNNRWTWVQ SNARLLYKNG RPDYIIVTQR PLTDEEGTEH LRKR NTKLP FMFTTGEAVL YEATNPFPAI MDPLPLRTKN GTSG UniProtKB: Aryl hydrocarbon receptor |
-Macromolecule #4: MOLYBDATE ION
Macromolecule | Name: MOLYBDATE ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MOO |
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Molecular weight | Theoretical: 159.938 Da |
Chemical component information | ChemComp-MOO: |
-Macromolecule #5: ADENOSINE-5'-DIPHOSPHATE
Macromolecule | Name: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 2 / Formula: ADP |
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Molecular weight | Theoretical: 427.201 Da |
Chemical component information | ChemComp-ADP: |
-Macromolecule #6: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Macromolecule #7: benzo[a]pyrene
Macromolecule | Name: benzo[a]pyrene / type: ligand / ID: 7 / Number of copies: 1 / Formula: W62 |
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Molecular weight | Theoretical: 252.309 Da |
Chemical component information | ChemComp-W62: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.18 mg/mL | |||||||||||||||||||||
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Buffer | pH: 7 Component:
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Grid | Model: C-flat-1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 10 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 4.5 kPa | |||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9849 / Average exposure time: 2.0 sec. / Average electron dose: 1.1 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |