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- PDB-4ghi: Crystal structure of the high affinity heterodimer of HIF2 alpha ... -

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Basic information

Entry
Database: PDB / ID: 4ghi
TitleCrystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
KeywordsTRANSCRIPTION / PAS Fold / protein : protein interactions
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 / blood vessel remodeling / embryonic placenta development / Endogenous sterols / cis-regulatory region sequence-specific DNA binding / positive regulation of endothelial cell proliferation / NPAS4 regulates expression of target genes / regulation of heart rate / positive regulation of erythrocyte differentiation / visual perception / positive regulation of glycolytic process / Pexophagy / erythrocyte differentiation / mitochondrion organization / 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 / 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 / positive regulation of cold-induced thermogenesis / Neddylation / 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 / transcription regulator complex / sequence-specific DNA binding / response to oxidative stress / cell differentiation / nuclear body / response to hypoxia / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / protein heterodimerization activity / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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) ...: / 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 / Beta-Lactamase / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-0X3 / 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: 1.5 Å
AuthorsScheuermann, T.H. / Key, J. / Tambar, U.K. / Bruick, R.K. / Gardner, K.H.
CitationJournal: Nat.Chem.Biol. / Year: 2013
Title: Allosteric inhibition of hypoxia inducible factor-2 with small molecules.
Authors: Scheuermann, T.H. / Li, Q. / Ma, H.W. / Key, J. / Zhang, L. / Chen, R. / Garcia, J.A. / Naidoo, J. / Longgood, J. / Frantz, D.E. / Tambar, U.K. / Gardner, K.H. / Bruick, R.K.
History
DepositionAug 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2013Group: Database references
Revision 1.2Sep 13, 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 / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 650HELIX DETERMINATION METHOD: AUTHOR DETERMINED

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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)28,0903
Polymers27,7812
Non-polymers3091
Water3,315184
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint-11 kcal/mol
Surface area10640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.353, 83.000, 41.020
Angle α, β, γ (deg.)90.00, 105.98, 90.00
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 / HIF-2-alpha / HIF2-alpha / Member of PAS protein 2 / PAS domain-containing protein 2


Mass: 13538.300 Da / Num. of mol.: 1 / Fragment: C-terminal PAS domain, UNP residues 239-350 / Mutation: R247E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BHLHE73, EPAS1, HIF2A, MOP2, PASD2 / Plasmid: pHIS-GB1-parallel / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)CodonPlus / 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 / HIF-1-beta / HIF1-beta


Mass: 14243.098 Da / Num. of mol.: 1 / Fragment: C-terminal PAS domain, UNP residues 356-470 / Mutation: E362R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARNT, BHLHE2 / Plasmid: pHIS-GB1-parallel / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)CodonPlus / References: UniProt: P27540
#3: Chemical ChemComp-0X3 / N-(3-chloro-5-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine


Mass: 308.652 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H6ClFN4O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE BOUND INHIBITOR CORRESPONDS TO COMPOUND (2) IN THE PRIMARY LITERATURE CITATION

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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: 2.16 Å3/Da / Density % sol: 43.07 %
Crystal growTemperature: 293 K / pH: 6
Details: 20% PEG400 50 mM BisTris, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97937
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 16, 2010
RadiationMonochromator: CUSTOM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97937 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 37413 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 4.7 % / Rmerge(I) obs: 0.041 / Rsym value: 0.041 / Net I/σ(I): 30.7
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.408 / Mean I/σ(I) obs: 2 / % possible all: 89.9

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHENIX(phenix.refine: 1.7.2_869)model building
PHENIX(phenix.refine: 1.7.2_869)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.7.2_869phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3F1P

3f1p


Resolution: 1.5→29.02 Å / SU ML: 0.32 / σ(F): 1.36 / Phase error: 18.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.196 1880 5.03 %
Rwork0.169 --
obs0.17 37409 98.9 %
all-37413 -
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.48 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.6947 Å2-0 Å2-0.9053 Å2
2---1.9307 Å2-0 Å2
3----0.764 Å2
Refinement stepCycle: LAST / Resolution: 1.5→29.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1782 0 21 184 1987
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112028
X-RAY DIFFRACTIONf_angle_d1.3122758
X-RAY DIFFRACTIONf_dihedral_angle_d15.859757
X-RAY DIFFRACTIONf_chiral_restr0.078285
X-RAY DIFFRACTIONf_plane_restr0.006360
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.53970.30671120.25842467X-RAY DIFFRACTION90
1.5397-1.5850.27091440.21732703X-RAY DIFFRACTION98
1.585-1.63610.24121340.20382762X-RAY DIFFRACTION100
1.6361-1.69460.2261410.18092733X-RAY DIFFRACTION100
1.6946-1.76240.221670.16912732X-RAY DIFFRACTION100
1.7624-1.84260.20641530.16742774X-RAY DIFFRACTION100
1.8426-1.93980.20911560.1632719X-RAY DIFFRACTION100
1.9398-2.06130.16331460.15732772X-RAY DIFFRACTION100
2.0613-2.22040.17831420.15422765X-RAY DIFFRACTION100
2.2204-2.44370.18141250.15822799X-RAY DIFFRACTION100
2.4437-2.79710.19381530.16642733X-RAY DIFFRACTION100
2.7971-3.5230.17731590.16282763X-RAY DIFFRACTION100
3.523-29.02710.19921480.172807X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.0854-3.0773-4.20013.12064.39576.6379-0.130.225-0.04160.14460.1309-0.1560.54910.3707-0.09770.1447-0.00540.01560.2043-0.04350.125219.512-52.88568.1499
26.58990.4673-2.86083.55370.77133.9677-0.0696-0.09370.04220.3468-0.1221-0.46770.02730.30010.13710.1286-0.0225-0.05160.13220.02920.20320.7688-44.972916.1016
30.26541.019-1.37585.982-6.54729.1684-0.091-0.02510.07010.1968-0.1186-0.2596-0.195-0.01870.23690.1656-0.0376-0.05920.1346-0.02650.200118.0995-35.819812.9339
48.10926.0554-5.58056.9611-3.71136.20680.43190.3720.57540.209-0.04270.784-0.7567-0.599-0.29150.18590.0509-0.050.1905-0.00870.25486.8936-35.65116.2385
51.3452-1.2992-1.2262.9332-0.48094.5108-0.10.2575-0.018-0.2032-0.107-0.2632-0.0973-0.01110.14380.1031-0.0057-0.00470.0820.00060.139115.8936-42.8055.8713
62.4050.0354-0.64694.6715-0.03943.35180.11430.09980.0218-0.1964-0.1372-0.0271-0.18250.01930.00240.1036-0.0170.00690.0936-0.03060.131213.8644-46.88219.405
73.61670.4051-0.31258.3742-3.92286.7884-0.01190.09810.14270.21340.14240.1597-0.3253-0.2151-0.12150.09880.00330.01310.0922-0.01710.058811.74-58.5220.533
83.06762.65721.88564.16042.71015.83650.1121-0.1210.1629-0.0872-0.19380.2963-0.0884-0.49610.07040.11010.0257-0.00240.17930.01340.125316.997-58.86928.722
98.9107-0.1679-1.24661.48210.81863.30290.13760.0259-0.09910.0712-0.03980.01110.4016-0.0618-0.0780.2119-0.0269-0.01630.0706-0.00560.08877.003-68.1625.742
102.67080.731.47993.49773.38924.9530.2471-0.3147-0.32690.2778-0.0430.05820.5153-0.2167-0.12730.175-0.0282-0.01980.10680.02260.1232-0.721-66.27216.54
117.6045-5.39623.28558.4637-5.41763.4742-0.6841-0.91540.38651.2368-0.3442-0.5812-0.5110.07410.6510.22770.0132-0.01570.2583-0.01920.1559-1.635-55.5048.825
121.3366-0.447-1.11291.54871.10944.64130.0412-0.0274-0.01610.02130.06970.0042-0.05420.0712-0.11690.09620.0160.01030.06990.00830.06794.588-60.5426.913
130.62480.092-0.14081.06351.07884.01330.15960.1923-0.0085-0.9789-0.1203-0.26530.18160.2271-0.03090.33720.0660.06980.1284-0.0064-0.054611.249-58.9351.015
143.2987-0.1815-3.06962.6912-1.46128.54580.22140.01190.17310.11040.02750.0244-0.5105-0.0858-0.28120.0963-0.0087-0.01350.0582-0.01190.06154.635-55.6523.847
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 0:248)
2X-RAY DIFFRACTION2chain 'A' and (resseq 249:272)
3X-RAY DIFFRACTION3chain 'A' and (resseq 273:282)
4X-RAY DIFFRACTION4chain 'A' and (resseq 283:299)
5X-RAY DIFFRACTION5chain 'A' and (resseq 300:326)
6X-RAY DIFFRACTION6chain 'A' and (resseq 327:348)
7X-RAY DIFFRACTION7chain 'B' and (resseq 358:377)
8X-RAY DIFFRACTION8chain 'B' and (resseq 378:390)
9X-RAY DIFFRACTION9chain 'B' and (resseq 391:404)
10X-RAY DIFFRACTION10chain 'B' and (resseq 405:417)
11X-RAY DIFFRACTION11chain 'B' and (resseq 418:422)
12X-RAY DIFFRACTION12chain 'B' and (resseq 423:446)
13X-RAY DIFFRACTION13chain 'B' and (resseq 447:455)
14X-RAY DIFFRACTION14chain 'B' and (resseq 456:467)

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