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- PDB-4gs9: Crystal structure of the high affinity heterodimer of HIF2 alpha ... -

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Basic information

Entry
Database: PDB / ID: 4gs9
TitleCrystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with an inactive benzoxadiazole antagonist
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
KeywordsTRANSCRIPTION / PAS fold / protein-protein interactions / nucleus
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-0XB / 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL / Aryl hydrocarbon receptor nuclear translocator / Endothelial PAS domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.72 Å
AuthorsScheuermann, T.H. / Gardner, K.H.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Development of Inhibitors of the PAS-B Domain of the HIF-2 alpha Transcription Factor
Authors: Rogers, J.L. / Bayeh, L. / Scheuermann, T.H. / Longgood, J. / Key, J. / Naidoo, J. / Melito, L. / Shokri, C. / Frantz, D.E. / Bruick, R.K. / Gardner, K.H. / Macmillan, J.B. / Tambar, U.K.
History
DepositionAug 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2013Provider: repository / Type: Initial release
Revision 1.1May 30, 2018Group: Advisory / Data collection / Derived calculations
Category: pdbx_distant_solvent_atoms / pdbx_struct_assembly_gen ...pdbx_distant_solvent_atoms / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues
Item: _pdbx_struct_assembly_prop.value
Revision 1.2Sep 13, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / 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)28,4264
Polymers27,7812
Non-polymers6452
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2350 Å2
ΔGint-12 kcal/mol
Surface area10590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.745, 83.054, 41.075
Angle α, β, γ (deg.)90.00, 105.78, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-580-

HOH

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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: HIF2 PAS-B domain, UNP residues 239-350 / Mutation: R247E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BHLHE73, EPAS1, HIF2, HIF2A, MOP2, PASD2 / Plasmid: pHIS-GB1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) CondonPlus / 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: ARNT PAS-B 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 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) CondonPlus / References: UniProt: P27540
#3: Chemical ChemComp-0XB / N-(3-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine


Mass: 274.207 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H7FN4O3
#4: Chemical ChemComp-PE8 / 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL


Mass: 370.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H34O9
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE SMALL MOLECULE LIGAND BOUND TO THE HIF2ALPHA PAS-B DOMAIN IN THIS ENTRY IS IDENTICAL TO ...THE SMALL MOLECULE LIGAND BOUND TO THE HIF2ALPHA PAS-B DOMAIN IN THIS ENTRY IS IDENTICAL TO COMPOUND (23), WHICH DESCRIBED IN THE PRIMARY PUBLICATION ASSOCIATED WITH THIS ENTRY

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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: 2.15 Å3/Da / Density % sol: 42.76 %
Crystal growTemperature: 293 K / pH: 6
Details: 20% PEG 3350 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: 0.9717767
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 17, 2010
RadiationMonochromator: CUSTOM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9717767 Å / Relative weight: 1
ReflectionResolution: 1.72→50 Å / Num. obs: 24715 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 4.4 % / Rmerge(I) obs: 0.036 / Net I/σ(I): 36.2
Reflection shellResolution: 1.72→1.75 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.282 / Mean I/σ(I) obs: 4.3 / % possible all: 98.5

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHENIXmodel building
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3F1P

3f1p


Resolution: 1.72→30.67 Å / SU ML: 0.24 / σ(F): 1.37 / Phase error: 20.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.202 1279 5.17 %
Rwork0.174 --
obs0.175 24715 99.1 %
all-24724 -
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 55.33 Å2 / ksol: 0.41 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.9111 Å2-0 Å2-0.3106 Å2
2---3.0753 Å2-0 Å2
3---0.1643 Å2
Refinement stepCycle: LAST / Resolution: 1.72→30.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1773 0 45 121 1939
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092012
X-RAY DIFFRACTIONf_angle_d1.1962724
X-RAY DIFFRACTIONf_dihedral_angle_d17.282761
X-RAY DIFFRACTIONf_chiral_restr0.076281
X-RAY DIFFRACTIONf_plane_restr0.005349
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7205-1.78930.31221700.2352499X-RAY DIFFRACTION97
1.7893-1.87080.24831350.20972594X-RAY DIFFRACTION99
1.8708-1.96940.2371510.1812615X-RAY DIFFRACTION99
1.9694-2.09270.19561220.16372607X-RAY DIFFRACTION100
2.0927-2.25430.19211420.16572600X-RAY DIFFRACTION100
2.2543-2.4810.19591250.16222630X-RAY DIFFRACTION100
2.481-2.83980.20731430.17132637X-RAY DIFFRACTION100
2.8398-3.5770.17811560.16242614X-RAY DIFFRACTION100
3.577-30.6740.19721350.17752640X-RAY DIFFRACTION98
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)
15.7363-2.4619-4.09247.11313.66787.676-0.29360.4723-0.6645-0.06290.1202-0.29910.69040.40320.13030.2151-0.02890.00690.3178-0.10640.28819.2428-52.41548.2445
24.3064-3.9194-1.79953.91420.80977.27860.1080.0863-0.04790.5573-0.25380.1546-0.3565-0.14310.09960.2016-0.0577-0.01420.1426-0.04540.216213.8207-42.069617.9956
37.87085.73-3.43577.1712-0.04329.0545-0.03110.0597-1.47840.3103-0.1315-1.55380.68970.20230.24240.20980.0004-0.08270.29190.00910.52125.1604-49.779911.374
41.63520.2876-2.58026.498-0.96134.9527-0.0052-0.1712-0.10390.3967-0.06-0.6780.01330.20350.11940.2177-0.0588-0.10310.174-0.01360.294221.2152-38.802314.6128
58.3146.5347-6.15148.0992-5.10328.1373-0.0410.44111.08610.07640.30020.7905-0.509-0.6205-0.20290.20040.028-0.08350.19830.00850.29517.0468-35.93896.3199
63.1994-0.0418-2.5163.9517-0.82044.3674-0.1540.2194-0.0496-0.2053-0.0399-0.398-0.13460.15820.1310.1543-0.0364-0.01320.1771-0.00440.166816.3238-42.35925.4721
75.45460.7224-1.31066.5616-0.17417.12110.01850.06670.0134-0.1623-0.0866-0.1107-0.12130.20510.12130.1383-0.0217-0.02770.1012-0.02280.13813.2787-46.543110.1229
85.9565-0.84231.70076.6919-1.40913.2721-0.11050.0790.0220.39990.160.0104-0.2692-0.1908-0.10350.2027-0.00150.01640.1592-0.03470.099112.023-59.60719.556
94.7882-0.53582.09629.0622-0.62836.56560.16180.18260.1125-0.3416-0.14240.5249-0.2991-0.6876-0.03770.16560.064-0.03090.2184-0.01280.157415.599-55.1528.713
104.3781-2.32483.06838.3962-5.26657.95130.3818-0.3274-0.0646-0.44340.17370.51480.7922-1.0836-0.46950.2008-0.0657-0.00350.30720.00690.182917.186-64.69925.931
113.88740.7623.09523.09753.36054.92980.2577-0.1541-0.34920.2232-0.0353-0.03870.4447-0.0293-0.19310.183-0.0294-0.01370.10350.01790.12341.131-67.07221.038
122.9592-1.96470.90828.0831-4.39512.3925-0.5412-0.96040.44141.0808-0.4334-0.2247-0.5076-0.37570.87370.35120.0532-0.00390.3747-0.05310.1932-1.429-55.2959.218
132.4056-0.4946-2.4541.78780.63345.6460.07530.1142-0.07110.03190.12130.0132-0.1588-0.0095-0.15070.15230.0256-0.00320.0960.01520.09814.521-60.40226.893
141.12110.86460.9470.81841.62846.1141-0.02390.27850.1591-1.35660.05170.06770.02250.4079-0.04850.40780.0530.05410.2315-0.00240.064411.12-58.8421.055
155.31772.2835-3.43775.0767-3.4383.26530.1369-0.0439-0.04930.1495-0.1808-0.1767-0.50390.3456-0.02830.1620.0061-0.01680.1489-0.0110.0873.716-55.27924.615
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 0:248)
2X-RAY DIFFRACTION2chain 'A' and (resseq 249:258)
3X-RAY DIFFRACTION3chain 'A' and (resseq 259:265)
4X-RAY DIFFRACTION4chain 'A' and (resseq 266:282)
5X-RAY DIFFRACTION5chain 'A' and (resseq 283:299)
6X-RAY DIFFRACTION6chain 'A' and (resseq 300:326)
7X-RAY DIFFRACTION7chain 'A' and (resseq 327:348)
8X-RAY DIFFRACTION8chain 'B' and (resseq 360:377)
9X-RAY DIFFRACTION9chain 'B' and (resseq 378:384)
10X-RAY DIFFRACTION10chain 'B' and (resseq 385:395)
11X-RAY DIFFRACTION11chain 'B' and (resseq 396:417)
12X-RAY DIFFRACTION12chain 'B' and (resseq 418:422)
13X-RAY DIFFRACTION13chain 'B' and (resseq 423:446)
14X-RAY DIFFRACTION14chain 'B' and (resseq 447:455)
15X-RAY DIFFRACTION15chain 'B' and (resseq 456:468)

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