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- PDB-6e3t: Crystal Structure of the Heterodimeric HIF-2 Complex with Antagon... -

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Basic information

Entry
Database: PDB / ID: 6e3t
TitleCrystal Structure of the Heterodimeric HIF-2 Complex with Antagonist T1001
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
Keywordstranscription/transcription inhibitor / Complex / Antagonist / Transcription factor / transcription-transcription inhibitor complex
Function / homology
Function and homology information


Cellular response to hypoxia / Phase I - Functionalization of compounds / Xenobiotics / Aryl hydrocarbon receptor signalling / NPAS4 regulates expression of target genes / Regulation of gene expression by Hypoxia-inducible Factor / myoblast fate commitment / Endogenous sterols / nuclear aryl hydrocarbon receptor complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha ...Cellular response to hypoxia / Phase I - Functionalization of compounds / Xenobiotics / Aryl hydrocarbon receptor signalling / NPAS4 regulates expression of target genes / Regulation of gene expression by Hypoxia-inducible Factor / myoblast fate commitment / Endogenous sterols / nuclear aryl hydrocarbon receptor complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / positive regulation of hormone biosynthetic process / regulation of protein neddylation / Neddylation / positive regulation of protein sumoylation / norepinephrine metabolic process / surfactant homeostasis / epithelial cell maturation / hemopoiesis / aryl hydrocarbon receptor binding / blood vessel remodeling / positive regulation of vascular endothelial growth factor production / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / visual perception / regulation of heart rate / erythrocyte differentiation / positive regulation of glycolytic process / mitochondrion organization / lung development / mRNA transcription by RNA polymerase II / transcription coactivator binding / multicellular organismal-level iron ion homeostasis / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / response to toxic substance / nuclear receptor activity / sequence-specific double-stranded DNA binding / positive regulation of cold-induced thermogenesis / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to oxidative stress / gene expression / angiogenesis / cellular response to hypoxia / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / response to oxidative stress / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation / response to hypoxia / nuclear speck / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein heterodimerization activity / DNA-binding transcription factor activity / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / DNA binding / nucleus / cytoplasm
Similarity search - Function
Hypoxia-inducible factor 1-alpha bHLH domain / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold / Helix-loop-helix DNA-binding domain / PAC motif ...Hypoxia-inducible factor 1-alpha bHLH domain / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold / Helix-loop-helix DNA-binding domain / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / PAS domain / 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 / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily
Similarity search - Domain/homology
Chem-HO7 / Aryl hydrocarbon receptor nuclear translocator / Endothelial PAS domain-containing protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsWu, D. / Su, X. / Lu, J. / Li, S. / Hood, B. / Vasile, S. / Potluri, N. / Diao, X. / Kim, Y. / Khorasanizadeh, S. / Rastinejad, F.
Funding support United States, China, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01GM117013, R01DK118297 United States
National Science Foundation (NSF, China)31700114 China
CitationJournal: Nat. Chem. Biol. / Year: 2019
Title: Bidirectional modulation of HIF-2 activity through chemical ligands.
Authors: Wu, D. / Su, X. / Lu, J. / Li, S. / Hood, B.L. / Vasile, S. / Potluri, N. / Diao, X. / Kim, Y. / Khorasanizadeh, S. / Rastinejad, F.
History
DepositionJul 15, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 3, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Aryl hydrocarbon receptor nuclear translocator
B: Endothelial PAS domain-containing protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,9933
Polymers85,7092
Non-polymers2831
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6840 Å2
ΔGint-52 kcal/mol
Surface area24750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.032, 97.981, 77.427
Angle α, β, γ (deg.)90.00, 107.10, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Aryl hydrocarbon receptor nuclear translocator / ARNT protein / Dioxin receptor / nuclear translocator / Hypoxia-inducible factor 1-beta / HIF1-beta


Mass: 43437.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Arnt / Plasmid: pMKH / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P53762
#2: Protein Endothelial PAS domain-containing protein 1 / EPAS-1 / HIF-1-alpha-like factor / mHLF / HIF-related factor / HRF / Hypoxia-inducible factor 2- ...EPAS-1 / HIF-1-alpha-like factor / mHLF / HIF-related factor / HRF / Hypoxia-inducible factor 2-alpha / HIF2-alpha


Mass: 42272.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Epas1, Hif2a / Plasmid: pSJ2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P97481
#3: Chemical ChemComp-HO7 / (6S)-6-(4-bromophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole


Mass: 283.187 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11BrN2S / Feature type: SUBJECT OF INVESTIGATION

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.07 Å3/Da / Density % sol: 40.7 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 2% TACSIMATE, PH 7.0, 6% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97929 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.96→50 Å / Num. obs: 14016 / % possible obs: 94.3 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 18.7
Reflection shellResolution: 2.96→3.01 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.714 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1077 / % possible all: 71.1

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Processing

Software
NameVersionClassification
PHENIX(dev_2467: ???)refinement
HKL-3000data collection
HKL-3000data scaling
PHASERphasing
HKL-3000data processing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZP4

4zp4


Resolution: 3→41.793 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 40.58
RfactorNum. reflection% reflection
Rfree0.3064 637 4.75 %
Rwork0.2455 --
obs0.2485 13415 95.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3→41.793 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4251 0 15 0 4266
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0124362
X-RAY DIFFRACTIONf_angle_d1.5865882
X-RAY DIFFRACTIONf_dihedral_angle_d6.4122616
X-RAY DIFFRACTIONf_chiral_restr0.08669
X-RAY DIFFRACTIONf_plane_restr0.009735
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.0001-3.23170.38881170.31052376X-RAY DIFFRACTION89
3.2317-3.55670.38091120.28342608X-RAY DIFFRACTION97
3.5567-4.0710.34121310.26342636X-RAY DIFFRACTION98
4.071-5.12760.27651460.21942587X-RAY DIFFRACTION98
5.1276-41.7970.29041310.23812571X-RAY DIFFRACTION94
Refinement TLS params.Method: refined / Origin x: -15.7549 Å / Origin y: 21.1339 Å / Origin z: -7.5814 Å
111213212223313233
T0.4555 Å2-0.015 Å2-0.0035 Å2-0.73 Å20.0483 Å2--0.6935 Å2
L1.3672 °2-0.0187 °20.3281 °2-1.8698 °20.6761 °2--3.7178 °2
S-0.0973 Å °-0.4097 Å °0.0471 Å °-0.0474 Å °-0.1719 Å °0.1697 Å °-0.2152 Å °-0.7866 Å °0.2495 Å °
Refinement TLS groupSelection details: all

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