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- PDB-5tbm: Crystal structure of PT2385 bound to HIF2a-B*:ARNT-B* complex -

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Basic information

Entry
Database: PDB / ID: 5tbm
TitleCrystal structure of PT2385 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 / regulation of heart rate / positive regulation of glycolytic process / 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 / transcription coactivator binding / multicellular organismal-level iron ion homeostasis / 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 / response to oxidative stress / RNA polymerase II-specific DNA-binding transcription factor binding / 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 / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein heterodimerization activity / 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 / cytosol / 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 / 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-79A / Aryl hydrocarbon receptor nuclear translocator / Endothelial PAS domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsDu, X.
CitationJournal: Cancer Res. / Year: 2016
Title: A Small-Molecule Antagonist of HIF2 alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.
Authors: Wallace, E.M. / Rizzi, J.P. / Han, G. / Wehn, P.M. / Cao, Z. / Du, X. / Cheng, T. / Czerwinski, R.M. / Dixon, D.D. / Goggin, B.S. / Grina, J.A. / Halfmann, M.M. / Maddie, M.A. / Olive, S.R. ...Authors: Wallace, E.M. / Rizzi, J.P. / Han, G. / Wehn, P.M. / Cao, Z. / Du, X. / Cheng, T. / Czerwinski, R.M. / Dixon, D.D. / Goggin, B.S. / Grina, J.A. / Halfmann, M.M. / Maddie, M.A. / Olive, S.R. / Schlachter, S.T. / Tan, H. / Wang, B. / Wang, K. / Xie, S. / Xu, R. / Yang, H. / Josey, J.A.
History
DepositionSep 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2016Group: Database references
Revision 1.2Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)27,4323
Polymers27,0492
Non-polymers3831
Water28816
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Endothelial PAS domain-containing protein 1
hetero molecules

B: Aryl hydrocarbon receptor nuclear translocator


Theoretical massNumber of molelcules
Total (without water)27,4323
Polymers27,0492
Non-polymers3831
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_544-x+1/2,y-1/2,-z-11
Buried area1720 Å2
ΔGint-8 kcal/mol
Surface area10770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.400, 84.097, 41.401
Angle α, β, γ (deg.)90.000, 106.240, 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 237-248
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPAS1, BHLHE73, HIF2A, MOP2, PASD2 / Production host: Escherichia coli (E. coli) / 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 340-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARNT, BHLHE2 / Production host: Escherichia coli (E. coli) / References: UniProt: P27540
#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
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 2.37 Å3/Da / Density % sol: 48.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.4
Details: 50 mM Bis-Tris pH5.4, 16% PEG 3350. use freshly crushed crystal as seed.

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Data collection

DiffractionMean temperature: 77.2 K / Ambient temp details: liquis nitrogen vapor
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9792 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: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.85→28.89 Å / Num. obs: 20307 / % possible obs: 98.6 % / Redundancy: 3.5 % / Rpim(I) all: 0.073 / Net I/av σ(I): 16.8 / Net I/σ(I): 269
Reflection shell
Resolution (Å)Rmerge(I) obsMean I/σ(I) obsCC1/2Diffraction-ID% possible all
5.02-700.035510.999193.2
3.99-5.020.031511199.7
3.48-3.990.034440.999199.8
3.16-3.480.045360.999199.9
2.94-3.160.061280.9991100
2.76-2.940.08210.9991100
2.63-2.760.1010.998199.9
2.51-2.630.12312.70.997199.9
2.41-2.510.13810.70.9971
2.33-2.410.1877.630.9951
2.26-2.330.2535.30.991100
2.19-2.260.284.80.9851100
2.14-2.190.3434.10.9811100
2.08-2.140.3853.60.9761100
2.04-2.080.4363.050.973199.7
1.99-2.040.5192.40.961199.5
1.95-1.990.6751.80.944198.7
1.92-1.950.7540.921197.7
1.88-1.920.8641.10.907193.9
1.85-1.881.0770.880.89190.7

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.2data extraction
SCALEPACKdata scaling
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XT2

4xt2


Resolution: 1.85→28.89 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.923 / SU B: 5.696 / SU ML: 0.163 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.175 / ESU R Free: 0.174
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2997 1057 5.2 %RANDOM
Rwork0.2375 ---
obs0.2406 19304 98.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 108.64 Å2 / Biso mean: 42.799 Å2 / Biso min: 21.63 Å2
Baniso -1Baniso -2Baniso -3
1-4.1 Å20 Å2-0.08 Å2
2---1.09 Å20 Å2
3----3.05 Å2
Refinement stepCycle: final / Resolution: 1.85→28.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1773 0 26 16 1815
Biso mean--33.24 40.32 -
Num. residues----216
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.021853
X-RAY DIFFRACTIONr_angle_refined_deg2.1091.9492510
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1125215
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.5824.27196
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.99915319
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0041510
X-RAY DIFFRACTIONr_chiral_restr0.140.2267
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211411
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.439 71 -
Rwork0.382 1284 -
all-1355 -
obs--90.51 %

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