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- PDB-8ck4: STRUCTURE OF HIF2A-ARNT HETERODIMER IN COMPLEX WITH (4S)-1-(3,5-d... -

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Basic information

Entry
Database: PDB / ID: 8ck4
TitleSTRUCTURE OF HIF2A-ARNT HETERODIMER IN COMPLEX WITH (4S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
KeywordsTRANSCRIPTION / HYPOXIA-INDUCIBLE FACTOR / BHLH-PAS / HIF-2-ALPHA / ARNT
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 / epithelial cell maturation / Phase I - Functionalization of compounds / positive regulation of vascular endothelial growth factor receptor signaling pathway / 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 / NPAS4 regulates expression of target genes / Pexophagy / visual perception / positive regulation of endothelial cell proliferation / 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 / transcription coactivator binding / PPARA activates gene expression / 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 / cellular response to oxidative stress / Neddylation / positive regulation of cold-induced thermogenesis / cellular response to hypoxia / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / response to oxidative stress / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / cell differentiation / response to hypoxia / nuclear body / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein heterodimerization 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 / 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 DNA-binding domain superfamily ...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 / 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 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. / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily
Similarity search - Domain/homology
Chem-UY3 / 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: 2.29 Å
AuthorsMusil, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of Cycloalkyl[ c ]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2 alpha Inhibitors.
Authors: Buchstaller, H.P. / Sala-Hojman, A. / Leiendecker, M. / Albers, J. / Anlauf, U. / Berges, N. / Dong, L. / Fuchss, T. / Germann, M. / Knehans, T. / Krier, M. / Lecomte, M. / Muller, D. / ...Authors: Buchstaller, H.P. / Sala-Hojman, A. / Leiendecker, M. / Albers, J. / Anlauf, U. / Berges, N. / Dong, L. / Fuchss, T. / Germann, M. / Knehans, T. / Krier, M. / Lecomte, M. / Muller, D. / Muller, S.R. / Leuthner, B. / Lindemann, R. / Musil, D. / Nowak, M. / Reither, V. / Rettig, C. / Schindler, C.E.M. / Pakulska, U. / Spuck, D. / Wegener, A. / Zarebski, A.
History
DepositionFeb 14, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 19, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2023Group: 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

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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)28,2763
Polymers27,8962
Non-polymers3801
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint-10 kcal/mol
Surface area10780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.287, 83.765, 41.149
Angle α, β, γ (deg.)90.00, 106.59, 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: 13595.352 Da / Num. of mol.: 1
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 / HIF-1-beta / HIF1-beta


Mass: 14300.149 Da / Num. of mol.: 1
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-UY3 / (4~{S})-1-[3,5-bis(fluoranyl)phenyl]-5,5-bis(fluoranyl)-3-methylsulfonyl-6,7-dihydro-4~{H}-2-benzothiophen-4-ol


Mass: 380.378 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12F4O3S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.14 Å3/Da / Density % sol: 42.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 17% (w/v) PEG3350 ; 0.1 M BisTris pH 6.25

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.29→53.39 Å / Num. obs: 10254 / % possible obs: 96.1 % / Redundancy: 3.3 % / CC1/2: 0.996 / Rrim(I) all: 0.101 / Net I/σ(I): 9.92
Reflection shellResolution: 2.29→2.43 Å / Rmerge(I) obs: 0.644 / Num. unique obs: 1386 / CC1/2: 0.701

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.29→41.88 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.914 / SU R Cruickshank DPI: 0.391 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.365 / SU Rfree Blow DPI: 0.239 / SU Rfree Cruickshank DPI: 0.245
RfactorNum. reflection% reflectionSelection details
Rfree0.251 1039 10.15 %RANDOM
Rwork0.209 ---
obs0.213 10240 96.4 %-
Displacement parametersBiso mean: 51.17 Å2
Baniso -1Baniso -2Baniso -3
1--14.0091 Å20 Å2-4.0614 Å2
2--8.3893 Å20 Å2
3---5.6198 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.29→41.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1784 0 24 31 1839
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0071872HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.942542HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d655SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes333HARMONIC5
X-RAY DIFFRACTIONt_it1860HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.58
X-RAY DIFFRACTIONt_other_torsion17.5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion233SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1360SEMIHARMONIC4
LS refinement shellResolution: 2.29→2.31 Å
RfactorNum. reflection% reflection
Rwork0.3038 185 -
Rfree--9.76 %
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)
14.49730.2231-0.623.54590.03013.5795-0.14310.2124-0.140.0656-0.01840.0129-0.13010.12230.1615-0.0362-0.0608-0.0318-0.1335-0.0256-0.193115.8468-43.93329.5861
21.210.697-0.45251.0341-0.23953.01540.0035-0.0684-0.02890.02590.05920.0012-0.01770.078-0.06270.0693-0.00040.0277-0.1115-0.0064-0.16276.9686-61.297721.4182
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|235 - A|348 }
2X-RAY DIFFRACTION2{ B|360 - B|467 }

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