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- PDB-8ck3: STRUCTURE OF HIF2A-ARNT HETERODIMER IN COMPLEX WITH (S)-1-(3,5-Di... -

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Basic information

Entry
Database: PDB / ID: 8ck3
TitleSTRUCTURE OF HIF2A-ARNT HETERODIMER IN COMPLEX WITH (S)-1-(3,5-Difluoro-phenyl)-5,5-difluoro-3-methanesulfonyl-5,6-dihydro-4H-cyclopenta[c]thiophen-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 / 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 / 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-UXU / 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: 1.707 Å
AuthorsMusil, D. / Lehmannn, M. / Diehl, L.
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)28,3404
Polymers27,8962
Non-polymers4442
Water1,40578
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2040 Å2
ΔGint-7 kcal/mol
Surface area10900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.671, 83.594, 40.935
Angle α, β, γ (deg.)90, 106.86, 90
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-UXU / (4~{S})-1-[3,5-bis(fluoranyl)phenyl]-5,5-bis(fluoranyl)-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-4-ol


Mass: 366.351 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H10F4O3S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.13 Å3/Da / Density % sol: 42.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 22% PEG 3350, 0.1 M BIS TRIS pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99996 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99996 Å / Relative weight: 1
ReflectionResolution: 1.707→53.47 Å / Num. obs: 15973 / % possible obs: 62.7 % / Redundancy: 3.4 % / CC1/2: 0.999 / Rpim(I) all: 0.05 / Rrim(I) all: 0.072 / Net I/σ(I): 11.8
Reflection shellResolution: 1.707→1.905 Å / Num. unique obs: 799 / CC1/2: 0.512 / Rpim(I) all: 0.579

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.707→53.47 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.934 / SU R Cruickshank DPI: 0.196 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.192 / SU Rfree Blow DPI: 0.157 / SU Rfree Cruickshank DPI: 0.159
RfactorNum. reflection% reflectionSelection details
Rfree0.227 792 -RANDOM
Rwork0.197 ---
obs0.199 15973 62.7 %-
Displacement parametersBiso mean: 30.74 Å2
Baniso -1Baniso -2Baniso -3
1-3.5571 Å20 Å20.5043 Å2
2---1.0744 Å20 Å2
3----2.4827 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.707→53.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1802 0 27 78 1907
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0091975HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.062691HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d701SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes357HARMONIC5
X-RAY DIFFRACTIONt_it1965HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion246SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1682SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.12
X-RAY DIFFRACTIONt_other_torsion16.86
LS refinement shellResolution: 1.71→1.85 Å /
RfactorNum. reflection
Rfree0.241 22
Refinement TLS params.

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)
11.63470.2988-0.23083.12750.57852.4863-0.1334-0.0305-0.1856-0.03050.01420.0791-0.18560.07910.1192-0.0029-0.0523-0.0272-0.0555-0.0134-0.089615.6824-2.43229.6582
20.71260.383-0.30180.554-0.1421.58820.04280.01720.03830.01720.01180.10810.03830.1081-0.05460.0483-0.00530.0214-0.0456-0.0143-0.06346.7116-19.553220.991
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A235 - 349
2X-RAY DIFFRACTION2{ B|* }B361 - 467

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