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- PDB-5ufp: Crystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex -

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Basic information

Entry
Database: PDB / ID: 5ufp
TitleCrystal structure of PT2399 bound to HIF2a-B*:ARNT-B* complex
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
KeywordsTRANSCRIPTION / HIF2 inhibitor HIF2 ligand PAS-B hypoxia inducible factor 2 EPAS1
Function / homology
Function and homology information


myoblast fate commitment / nuclear aryl hydrocarbon receptor complex / Aryl hydrocarbon receptor signalling / positive regulation of hormone biosynthetic process / Cellular response to hypoxia / aryl hydrocarbon receptor complex / regulation of protein neddylation / Transcriptional regulation of pluripotent stem cells / PTK6 Expression / positive regulation of protein sumoylation ...myoblast fate commitment / nuclear aryl hydrocarbon receptor complex / Aryl hydrocarbon receptor signalling / positive regulation of hormone biosynthetic process / Cellular response to hypoxia / aryl hydrocarbon receptor complex / regulation of protein neddylation / Transcriptional regulation of pluripotent stem cells / PTK6 Expression / positive regulation of protein sumoylation / norepinephrine metabolic process / Xenobiotics / surfactant homeostasis / Phase I - Functionalization of compounds / positive regulation of vascular endothelial growth factor receptor signaling pathway / epithelial cell maturation / Regulation of gene expression by Hypoxia-inducible Factor / aryl hydrocarbon receptor binding / positive regulation of vascular endothelial growth factor production / embryonic placenta development / blood vessel remodeling / Endogenous sterols / cis-regulatory region sequence-specific DNA binding / positive regulation of endothelial cell proliferation / visual perception / NPAS4 regulates expression of target genes / Pexophagy / positive regulation of glycolytic process / regulation of heart rate / mitochondrion organization / erythrocyte differentiation / positive regulation of erythrocyte differentiation / RNA polymerase II transcription regulatory region sequence-specific DNA binding / lung development / mRNA transcription by RNA polymerase II / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / PPARA activates gene expression / multicellular organismal-level iron ion homeostasis / transcription coactivator binding / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / nuclear receptor activity / sequence-specific double-stranded DNA binding / Neddylation / positive regulation of cold-induced thermogenesis / cellular response to oxidative stress / cellular response to hypoxia / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / RNA polymerase II-specific DNA-binding transcription factor binding / response to oxidative stress / transcription regulator complex / sequence-specific DNA binding / cell differentiation / nuclear body / response to hypoxia / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / protein heterodimerization activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / chromatin / regulation of transcription by RNA polymerase II / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytoplasm / cytosol
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 / 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. / Beta-Lactamase / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-86D / Aryl hydrocarbon receptor nuclear translocator / Endothelial PAS domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsDu, X.
CitationJournal: Nature / Year: 2016
Title: On-target efficacy of a HIF-2 alpha antagonist in preclinical kidney cancer models.
Authors: Cho, H. / Du, X. / Rizzi, J.P. / Liberzon, E. / Chakraborty, A.A. / Gao, W. / Carvo, I. / Signoretti, S. / Bruick, R.K. / Josey, J.A. / Wallace, E.M. / Kaelin, W.G.
History
DepositionJan 5, 2017Deposition site: RCSB / Processing site: RCSB
SupersessionJan 25, 2017ID: 5T0T
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Endothelial PAS domain-containing protein 1
B: Aryl hydrocarbon receptor nuclear translocator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,4683
Polymers27,0492
Non-polymers4191
Water1,08160
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.379, 84.057, 41.472
Angle α, β, γ (deg.)90.000, 106.480, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Endothelial PAS domain-containing protein 1 / EPAS-1 / Basic-helix-loop-helix-PAS protein MOP2 / Class E basic helix-loop-helix protein 73 / ...EPAS-1 / Basic-helix-loop-helix-PAS protein MOP2 / Class E basic helix-loop-helix protein 73 / bHLHe73 / HIF-1-alpha-like factor / HLF / Hypoxia-inducible factor 2-alpha / HIF2-alpha / Member of PAS protein 2 / PAS domain-containing protein 2


Mass: 13278.995 Da / Num. of mol.: 1 / Fragment: UNP residues 239-348
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPAS1, BHLHE73, HIF2A, MOP2, PASD2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q99814
#2: Protein Aryl hydrocarbon receptor nuclear translocator / ARNT protein / Class E basic helix-loop-helix protein 2 / bHLHe2 / Dioxin receptor / nuclear ...ARNT protein / Class E basic helix-loop-helix protein 2 / bHLHe2 / Dioxin receptor / nuclear translocator / Hypoxia-inducible factor 1-beta / HIF1-beta


Mass: 13769.599 Da / Num. of mol.: 1 / Fragment: UNP residues 342-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARNT, BHLHE2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P27540
#3: Chemical ChemComp-86D / 3-({(1S)-7-[(difluoromethyl)sulfonyl]-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl}oxy)-5-fluorobenzonitrile


Mass: 419.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H10F5NO4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O

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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: 2.27 Å3/Da / Density % sol: 45.75 % / Description: RECTANGULAR RODS
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.4
Details: complex of HIF2-B*:ARNT-B* 10-12 mg/mL in 10 mM Tris-HCl, pH8.0 and 50 mM KCl; Crystallization buffer of 50 mM Bis-Tris, pH5.4 and 16% PEG3350.

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Data collection

DiffractionMean temperature: 77 K / Ambient temp details: liquid nitrogen vapor
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.9→28.89 Å / Num. obs: 18032 / % possible obs: 99.4 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.077 / Net I/σ(I): 16
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsCC1/2Diffraction-ID% possible all
3.99-503.60.032490.997198.5
3.17-3.993.50.041390.997199.9
2.77-3.173.60.085230.992199.7
2.51-2.773.60.133130.983199.8
2.33-2.513.60.198.20.973199.9
2.2-2.333.70.2925.30.9371100
2.09-2.23.70.3883.90.8851100
2-2.093.60.5212.80.806199.7
1.92-23.30.7771.60.655196.5
1.85-1.9230.99710.563196.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→28.89 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.934 / SU B: 5.307 / SU ML: 0.149 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.176 / ESU R Free: 0.168 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2712 975 5.1 %RANDOM
Rwork0.2177 ---
obs0.2206 18032 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 90.54 Å2 / Biso mean: 38.037 Å2 / Biso min: 19.3 Å2
Baniso -1Baniso -2Baniso -3
1-2.69 Å20 Å2-0.23 Å2
2---0.98 Å20 Å2
3----1.85 Å2
Refinement stepCycle: final / Resolution: 1.9→28.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1756 0 28 60 1844
Biso mean--31.12 43.44 -
Num. residues----214
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.021838
X-RAY DIFFRACTIONr_angle_refined_deg2.141.952490
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3815213
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.38124.21195
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.60315315
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1471510
X-RAY DIFFRACTIONr_chiral_restr0.150.2265
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211399
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.402 66 -
Rwork0.344 1283 -
all-1349 -
obs--98.9 %

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