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- PDB-7w80: Crystal Structure of the Heterodimeric HIF-2 in Complex with Anta... -

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Basic information

Entry
Database: PDB / ID: 7w80
TitleCrystal Structure of the Heterodimeric HIF-2 in Complex with Antagonist Belzutifan
Components
  • Aryl hydrocarbon receptor nuclear translocator
  • Endothelial PAS domain-containing protein 1
KeywordsTRANSCRIPTION / Hypoxia-inducible factor 2 / HIF-2alpha / ARNT
Function / homology
Function and homology information


Cellular response to hypoxia / Phase I - Functionalization of compounds / Xenobiotics / Aryl hydrocarbon receptor signalling / NPAS4 regulates expression of target genes / myoblast fate commitment / norepinephrine biosynthetic process / Regulation of gene expression by Hypoxia-inducible Factor / Endogenous sterols / nuclear aryl hydrocarbon receptor complex ...Cellular response to hypoxia / Phase I - Functionalization of compounds / Xenobiotics / Aryl hydrocarbon receptor signalling / NPAS4 regulates expression of target genes / myoblast fate commitment / norepinephrine biosynthetic process / Regulation of gene expression by Hypoxia-inducible Factor / Endogenous sterols / nuclear aryl hydrocarbon receptor complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / positive regulation of dopamine biosynthetic process / positive regulation of hormone biosynthetic process / aryl hydrocarbon receptor complex / regulation of protein neddylation / positive regulation of protein sumoylation / Neddylation / norepinephrine metabolic process / surfactant homeostasis / epithelial cell maturation / cobalt ion binding / aryl hydrocarbon receptor binding / hemopoiesis / positive regulation of vascular endothelial growth factor production / blood vessel remodeling / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / regulation of heart rate / visual perception / erythrocyte differentiation / mitochondrion organization / RNA polymerase II transcription regulatory region sequence-specific DNA binding / lung development / mRNA transcription by RNA polymerase II / transcription coactivator binding / response to toxic substance / 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 / cellular response to oxidative stress / cellular response to hypoxia / gene expression / 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 / transcription by RNA polymerase II / 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 / protein-containing complex binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / DNA binding / nucleus / 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 ...: / 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 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
Similarity search - Domain/homology
Chem-72Q / Aryl hydrocarbon receptor nuclear translocator / Endothelial PAS domain-containing protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.754 Å
AuthorsRen, X. / Diao, X. / Zhuang, J. / Wu, D.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Mol.Pharmacol. / Year: 2022
Title: Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan.
Authors: Ren, X. / Diao, X. / Zhuang, J. / Wu, D.
History
DepositionDec 7, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 21, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Structure summary / Category: chem_comp / citation_author / Item: _chem_comp.pdbx_synonyms / _citation_author.name
Revision 1.2Nov 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Aryl hydrocarbon receptor nuclear translocator
B: Endothelial PAS domain-containing protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,0223
Polymers84,6382
Non-polymers3831
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6990 Å2
ΔGint-49 kcal/mol
Surface area26320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.192, 98.187, 77.739
Angle α, β, γ (deg.)90.000, 107.160, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Aryl hydrocarbon receptor nuclear translocator / ARNT protein / Dioxin receptor / nuclear translocator / Hypoxia-inducible factor 1-beta / HIF-1- ...ARNT protein / Dioxin receptor / nuclear translocator / Hypoxia-inducible factor 1-beta / HIF-1-beta / HIF1-beta


Mass: 43437.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Arnt / Plasmid: pMKH / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P53762
#2: Protein Endothelial PAS domain-containing protein 1 / EPAS-1 / HIF-1-alpha-like factor / HLF / mHLF / HIF-related factor / HRF / Hypoxia-inducible factor ...EPAS-1 / HIF-1-alpha-like factor / HLF / mHLF / HIF-related factor / HRF / Hypoxia-inducible factor 2-alpha / HIF-2-alpha / HIF2-alpha


Mass: 41200.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Epas1, Hif2a / Plasmid: pSJ2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P97481
#3: Chemical ChemComp-72Q / 3-{[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl]oxy}-5-fluorobenzonitrile / Belzutifan


Mass: 383.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12F3NO4S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.12 Å3/Da / Density % sol: 41.96 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: Tacsimate, PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 6, 2020 / Details: mirrors
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.754→47 Å / Num. obs: 18363 / % possible obs: 99.8 % / Redundancy: 6.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.024 / Rrim(I) all: 0.062 / Net I/σ(I): 22.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.754-2.96.60.63526810.8880.2640.68899.3
8.71-475.80.01859910.0080.01998.5

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Processing

Software
NameVersionClassification
PHENIX1.20.1refinement
XDSJan 31, 2020data scaling
PDB_EXTRACT3.27data extraction
XDSJan 31, 2020data reduction
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZP4

4zp4


Resolution: 2.754→46.38 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 30.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2737 1820 9.93 %
Rwork0.2164 16502 -
obs0.2221 18322 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 198.82 Å2 / Biso mean: 87.4587 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.754→46.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4405 0 26 28 4459
Biso mean--59.51 73.59 -
Num. residues----552
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.7542-2.82870.43311310.3672124099
2.8287-2.91190.40611470.29421292100
2.9119-3.00590.3581370.26811252100
3.0059-3.11330.29951410.23451276100
3.1133-3.23790.27951480.2321263100
3.2379-3.38520.32421380.24991250100
3.3852-3.56360.27771430.23011282100
3.5636-3.78680.30941380.21551274100
3.7868-4.0790.23171420.20771260100
4.079-4.48920.22881390.18081275100
4.4892-5.13810.24421390.18031258100
5.1381-6.47060.26671370.23081292100
6.4706-46.380.27161400.2079128898
Refinement TLS params.Method: refined / Origin x: -2.0632 Å / Origin y: -17.9365 Å / Origin z: 29.7408 Å
111213212223313233
T0.3694 Å20.0166 Å20.0977 Å2-0.5282 Å20.014 Å2--0.4057 Å2
L1.0644 °20.359 °20.9395 °2-1.3138 °20.3009 °2--3.3973 °2
S-0.081 Å °-0.3221 Å °0.0871 Å °0.0126 Å °-0.0949 Å °0.0262 Å °-0.1517 Å °-0.5231 Å °0.1666 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA101 - 464
2X-RAY DIFFRACTION1allB30 - 401
3X-RAY DIFFRACTION1allS24 - 247

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