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- PDB-6e3u: Crystal Structure of the Heterodimeric HIF-2 Complex with Agonist... -

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Basic information

Entry
Database: PDB / ID: 6e3u
TitleCrystal Structure of the Heterodimeric HIF-2 Complex with Agonist M1001
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
Keywordstranscription/agonist / Complex / Agonist / Transcription factor / TRANSCRIPTION / transcription-agonist complex
Function / homology
Function and homology information


Cellular response to hypoxia / Xenobiotics / Aryl hydrocarbon receptor signalling / Phase I - Functionalization of compounds / 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 / Xenobiotics / Aryl hydrocarbon receptor signalling / Phase I - Functionalization of compounds / 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 / positive regulation of protein sumoylation / Neddylation / norepinephrine metabolic process / surfactant homeostasis / epithelial cell maturation / aryl hydrocarbon receptor binding / hemopoiesis / positive regulation of vascular endothelial growth factor production / blood vessel remodeling / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / visual perception / regulation of heart rate / lung development / positive regulation of glycolytic process / erythrocyte differentiation / mitochondrion organization / mRNA transcription by RNA polymerase II / multicellular organismal-level iron ion homeostasis / response to toxic substance / negative regulation of inflammatory response / transcription coactivator binding / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / positive regulation of cold-induced thermogenesis / cellular response to oxidative stress / response to oxidative stress / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / transcription regulator complex / cellular response to hypoxia / gene expression / sequence-specific DNA binding / RNA polymerase II-specific DNA-binding transcription factor 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 / DNA-binding transcription factor activity / protein heterodimerization 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
HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor 1-alpha bHLH domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold / Helix-loop-helix DNA-binding domain / PAC motif ...HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor 1-alpha bHLH 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-HNJ / 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: 2.85 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)85,9223
Polymers85,5942
Non-polymers3271
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7970 Å2
ΔGint-59 kcal/mol
Surface area25150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.951, 98.846, 77.077
Angle α, β, γ (deg.)90.00, 107.20, 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-HNJ / 3-{[2-(pyrrolidin-1-yl)phenyl]amino}-1H-1lambda~6~,2-benzothiazole-1,1-dione / (3-Chloro-Phenyl)-acetic acid (S)-1-(2-tert-butoxycarbonylamino-acetyl)-pyrrolidin-2-ylmethyl ester


Mass: 327.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N3O2S

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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: 40.9 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / 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 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 16131 / % possible obs: 98 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.093 / Net I/σ(I): 15.3
Reflection shellResolution: 2.85→2.9 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.741 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 818 / % possible all: 97.7

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
HKL-3000data collection
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZP4

4zp4


Resolution: 2.85→46.126 Å / SU ML: 0.42 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.63
RfactorNum. reflection% reflectionSelection details
Rfree0.2576 791 4.91 %Random selection
Rwork0.1986 ---
obs0.2015 16105 97.83 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.85→46.126 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4432 0 23 0 4455
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0114544
X-RAY DIFFRACTIONf_angle_d1.1456132
X-RAY DIFFRACTIONf_dihedral_angle_d5.4352779
X-RAY DIFFRACTIONf_chiral_restr0.06694
X-RAY DIFFRACTIONf_plane_restr0.007773
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8501-3.02860.32711370.26172526X-RAY DIFFRACTION98
3.0286-3.26240.31941200.2552592X-RAY DIFFRACTION99
3.2624-3.59060.29061370.21472554X-RAY DIFFRACTION99
3.5906-4.10990.25241280.19412585X-RAY DIFFRACTION98
4.1099-5.17690.2181250.17022540X-RAY DIFFRACTION98
5.1769-46.1320.25261440.19472517X-RAY DIFFRACTION95
Refinement TLS params.Method: refined / Origin x: 191.9192 Å / Origin y: -111.7561 Å / Origin z: 228.8478 Å
111213212223313233
T0.2834 Å2-0.0257 Å20.0632 Å2-0.4423 Å2-0.0187 Å2--0.5125 Å2
L1.2695 °2-0.5497 °20.5791 °2-1.7895 °2-0.9497 °2--3.3297 °2
S0.0429 Å °0.3093 Å °0.1762 Å °-0.0396 Å °-0.1203 Å °-0.0122 Å °-0.1543 Å °0.1043 Å °0.0909 Å °
Refinement TLS groupSelection details: all

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