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- PDB-4h6j: Identification of Cys 255 in HIF-1 as a novel site for developmen... -

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Basic information

Entry
Database: PDB / ID: 4h6j
TitleIdentification of Cys 255 in HIF-1 as a novel site for development of covalent inhibitors of HIF-1 /ARNT PasB domain protein-protein interaction.
Components
  • ARYL HYDROCARBON NUCLEAR TRANSLOCATOR
  • HYPOXIA INDUCIBLE FACTOR 1-ALPHA
KeywordsTRANSCRIPTION / PAS DOMAIN / HETERODIMER / HYPOXIA INDUCIBLE FACTOR / TRANSCRIPTION FACTOR / ARNT
Function / homology
Function and homology information


epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / hypoxia-inducible factor-1alpha signaling pathway / positive regulation of chemokine-mediated signaling pathway / elastin metabolic process / regulation of transforming growth factor beta2 production / glandular epithelial cell maturation / : / nuclear aryl hydrocarbon receptor complex ...epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / hypoxia-inducible factor-1alpha signaling pathway / positive regulation of chemokine-mediated signaling pathway / elastin metabolic process / regulation of transforming growth factor beta2 production / glandular epithelial cell maturation / : / nuclear aryl hydrocarbon receptor complex / hemoglobin biosynthetic process / cardiac ventricle morphogenesis / connective tissue replacement involved in inflammatory response wound healing / negative regulation of mesenchymal cell apoptotic process / negative regulation of growth / Aryl hydrocarbon receptor signalling / positive regulation of hormone biosynthetic process / aryl hydrocarbon receptor complex / intestinal epithelial cell maturation / Cellular response to hypoxia / retina vasculature development in camera-type eye / mesenchymal cell apoptotic process / regulation of protein neddylation / negative regulation of bone mineralization / PTK6 Expression / intracellular oxygen homeostasis / collagen metabolic process / B-1 B cell homeostasis / vascular endothelial growth factor production / positive regulation of protein sumoylation / dopaminergic neuron differentiation / Xenobiotics / transcription regulator activator activity / negative regulation of thymocyte apoptotic process / STAT3 nuclear events downstream of ALK signaling / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / lactate metabolic process / positive regulation of cytokine production involved in inflammatory response / Phase I - Functionalization of compounds / negative regulation of TOR signaling / insulin secretion involved in cellular response to glucose stimulus / positive regulation of vascular endothelial growth factor receptor signaling pathway / response to iron ion / neural crest cell migration / Regulation of gene expression by Hypoxia-inducible Factor / embryonic hemopoiesis / regulation of glycolytic process / motile cilium / DNA-binding transcription repressor activity / muscle cell cellular homeostasis / digestive tract morphogenesis / DNA-binding transcription activator activity / PTK6 promotes HIF1A stabilization / response to muscle activity / positive regulation of neuroblast proliferation / axonal transport of mitochondrion / bone mineralization / E-box binding / intracellular glucose homeostasis / heart looping / outflow tract morphogenesis / aryl hydrocarbon receptor binding / TOR signaling / positive regulation of insulin secretion involved in cellular response to glucose stimulus / positive regulation of macroautophagy / cellular response to interleukin-1 / positive regulation of epithelial cell migration / positive regulation of vascular endothelial growth factor production / neuroblast proliferation / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / Endogenous sterols / chondrocyte differentiation / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / positive regulation of chemokine production / positive regulation of endothelial cell proliferation / lactation / axon cytoplasm / NPAS4 regulates expression of target genes / positive regulation of nitric-oxide synthase activity / negative regulation of miRNA transcription / positive regulation of erythrocyte differentiation / positive regulation of glycolytic process / response to reactive oxygen species / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Hsp90 protein binding / transcription coactivator binding / euchromatin / PPARA activates gene expression / visual learning / cerebral cortex development / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cellular response to virus / positive regulation of miRNA transcription / NOTCH1 Intracellular Domain Regulates Transcription / negative regulation of inflammatory response / histone deacetylase binding / RNA polymerase II transcription regulator complex
Similarity search - Function
Hypoxia-inducible factor-1 alpha / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor 1-alpha bHLH domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold-3 / PAS fold ...Hypoxia-inducible factor-1 alpha / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor 1-alpha bHLH domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold-3 / 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 / 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 / Beta-Lactamase / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Aryl hydrocarbon receptor nuclear translocator / Hypoxia-inducible factor 1-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å
AuthorsCardoso, R. / Love, R.A. / Nilsson, C. / Bergqvist, S. / Nowlin, D. / Yan, J. / Liu, K. / Zhu, J. / Chen, P. / Deng, Y.-L. ...Cardoso, R. / Love, R.A. / Nilsson, C. / Bergqvist, S. / Nowlin, D. / Yan, J. / Liu, K. / Zhu, J. / Chen, P. / Deng, Y.-L. / Dyson, H.J. / Greig, M.J. / Brooun, A.
CitationJournal: Protein Sci. / Year: 2012
Title: Identification of Cys255 in HIF-1 alpha as a novel site for development of covalent inhibitors of HIF-1 alpha /ARNT PasB domain protein-protein interaction.
Authors: Cardoso, R. / Love, R. / Nilsson, C.L. / Bergqvist, S. / Nowlin, D. / Yan, J. / Liu, K.K. / Zhu, J. / Chen, P. / Deng, Y.L. / Dyson, H.J. / Greig, M.J. / Brooun, A.
History
DepositionSep 19, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: Database references
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Feb 28, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HYPOXIA INDUCIBLE FACTOR 1-ALPHA
B: ARYL HYDROCARBON NUCLEAR TRANSLOCATOR


Theoretical massNumber of molelcules
Total (without water)26,6922
Polymers26,6922
Non-polymers00
Water2,774154
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1770 Å2
ΔGint-9 kcal/mol
Surface area11040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.841, 44.940, 78.087
Angle α, β, γ (deg.)90.00, 96.54, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-576-

HOH

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Components

#1: Protein HYPOXIA INDUCIBLE FACTOR 1-ALPHA


Mass: 13051.650 Da / Num. of mol.: 1 / Fragment: PAS-B DOMAIN, UNP residues 238-348 / Mutation: R245E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIF-1 alpha / Plasmid: pCECC-N1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (AI) / References: UniProt: Q16665
#2: Protein ARYL HYDROCARBON NUCLEAR TRANSLOCATOR


Mass: 13640.396 Da / Num. of mol.: 1 / Fragment: PAS-B DOMAIN, UNP residues 357-470 / Mutation: E362R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARNT / Plasmid: pCECC-N1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (AI) / References: UniProt: P27540
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / Source method: isolated from a natural source / Formula: H2O

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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: 2.25 Å3/Da / Density % sol: 45.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 20% PEG 8000, 0.2M MgCl2, 0.1M Tris pH 8.5 , VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 10, 2011
RadiationMonochromator: CUSTOM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.52→38.8 Å / Num. all: 35783 / Num. obs: 35783 / % possible obs: 96.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.4 % / Biso Wilson estimate: 22.7 Å2 / Rmerge(I) obs: 0.047 / Rsym value: 0.047 / Net I/σ(I): 20.9
Reflection shellResolution: 1.52→1.6 Å / Redundancy: 5 % / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 3.5 / Num. unique all: 4270 / Rsym value: 0.43 / % possible all: 80

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Processing

Software
NameVersionClassification
CNSrefinement
CNX2005refinement
PROCESSdata reduction
SCALAdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.52→38.79 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 1013880.24 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.248 1776 5 %RANDOM
Rwork0.215 ---
obs0.216 35782 93.7 %-
all-35782 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.4093 Å2 / ksol: 0.395887 e/Å3
Displacement parametersBiso mean: 25 Å2
Baniso -1Baniso -2Baniso -3
1-1.86 Å20 Å23.77 Å2
2--0.16 Å20 Å2
3----2.02 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.17 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.52→38.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1783 0 0 154 1937
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d19.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.58
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.331.5
X-RAY DIFFRACTIONc_mcangle_it2.132
X-RAY DIFFRACTIONc_scbond_it2.072
X-RAY DIFFRACTIONc_scangle_it3.112.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.5→1.59 Å / Rfactor Rfree error: 0.023 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.335 213 5.3 %
Rwork0.289 3806 -
obs--63.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paraprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paradna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top

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