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- PDB-6e3s: Crystal Structure of the Heterodimeric HIF-2 Complex with Antagon... -

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Basic information

Entry
Database: PDB / ID: 6e3s
TitleCrystal Structure of the Heterodimeric HIF-2 Complex with Antagonist PT2385
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 / norepinephrine biosynthetic process / myoblast fate commitment / Regulation of gene expression by Hypoxia-inducible Factor / Endogenous sterols / nuclear aryl hydrocarbon receptor complex ...Cellular response to hypoxia / Phase I - Functionalization of compounds / Xenobiotics / Aryl hydrocarbon receptor signalling / NPAS4 regulates expression of target genes / norepinephrine biosynthetic process / myoblast fate commitment / Regulation of gene expression by Hypoxia-inducible Factor / Endogenous sterols / nuclear aryl hydrocarbon receptor complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / positive regulation of dopamine biosynthetic process / positive regulation of hormone biosynthetic process / aryl hydrocarbon receptor complex / regulation of protein neddylation / positive regulation of protein sumoylation / Neddylation / norepinephrine metabolic process / surfactant homeostasis / epithelial cell maturation / cobalt ion binding / aryl hydrocarbon receptor binding / hemopoiesis / positive regulation of vascular endothelial growth factor production / embryonic placenta development / blood vessel remodeling / cis-regulatory region sequence-specific DNA binding / visual perception / regulation of heart rate / mitochondrion organization / erythrocyte differentiation / RNA polymerase II transcription regulatory region sequence-specific DNA binding / lung development / mRNA transcription by RNA polymerase II / transcription coactivator binding / response to toxic substance / negative regulation of inflammatory response / multicellular organismal-level iron ion homeostasis / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / gene expression / cellular response to oxidative stress / positive regulation of cold-induced thermogenesis / cellular response to hypoxia / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / response to oxidative stress / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / transcription by RNA polymerase II / cell differentiation / response to hypoxia / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein heterodimerization activity / protein-containing complex binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
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 ...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 DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily
Similarity search - Domain/homology
Chem-79A / 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)85,9783
Polymers85,5942
Non-polymers3831
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6670 Å2
ΔGint-54 kcal/mol
Surface area25550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.009, 97.895, 77.965
Angle α, β, γ (deg.)90.00, 107.43, 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: 42156.961 Da / Num. of mol.: 1 / Mutation: W318A
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-79A / 3-{[(1S)-2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl]oxy}-5-fluorobenzonitrile / PT2385


Mass: 383.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12F3NO4S / 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: 2.08 Å3/Da / Density % sol: 41 %
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: Nov 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 14037 / % possible obs: 99 % / Redundancy: 2.6 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 11.4
Reflection shellResolution: 2.9→2.95 Å / Rmerge(I) obs: 0.765

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-3000data collection
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZP4

4zp4


Resolution: 3→48.948 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.01
RfactorNum. reflection% reflection
Rfree0.2491 697 4.97 %
Rwork0.2119 --
obs0.2139 14027 99.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3→48.948 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4366 0 26 0 4392
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.014490
X-RAY DIFFRACTIONf_angle_d1.2576063
X-RAY DIFFRACTIONf_dihedral_angle_d13.4262688
X-RAY DIFFRACTIONf_chiral_restr0.065683
X-RAY DIFFRACTIONf_plane_restr0.008761
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.23160.30121340.2412664X-RAY DIFFRACTION99
3.2316-3.55670.3221330.2372663X-RAY DIFFRACTION99
3.5567-4.07120.26581480.21652657X-RAY DIFFRACTION100
4.0712-5.12840.23011350.19482668X-RAY DIFFRACTION99
5.1284-48.9540.2341470.21122678X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 164.7007 Å / Origin y: -117.9064 Å / Origin z: 156.1202 Å
111213212223313233
T0.442 Å2-0.0152 Å20.0363 Å2-0.6941 Å2-0.0051 Å2--0.6434 Å2
L1.3368 °2-0.1949 °20.4041 °2-1.7799 °2-0.2483 °2--2.8747 °2
S-0.0466 Å °0.4455 Å °0.1326 Å °-0.0915 Å °-0.1971 Å °-0.0665 Å °-0.1442 Å °0.2593 Å °0.2386 Å °
Refinement TLS groupSelection details: all

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