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- PDB-2ilm: Factor Inhibiting HIF-1 Alpha D201A Mutant in Complex with FE(II)... -

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Basic information

Entry
Database: PDB / ID: 2ilm
TitleFactor Inhibiting HIF-1 Alpha D201A Mutant in Complex with FE(II), Alpha-Ketoglutarate and HIF-1 Alpha 35mer
Components(Hypoxia-inducible factor 1 ...) x 2
KeywordsTRANSCRIPTION REGULATOR / OXIDOREDUCTASE / FIH / HIF / DSBH / OXYGENASE / TRANSCRIPTION / HYPOXIA / INHIBITOR 2-OXOGLUTARATE / ASPARAGINYL HYDROXYLASE
Function / homology
Function and homology information


epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / positive regulation of chemokine-mediated signaling pathway / hypoxia-inducible factor-1alpha signaling pathway / elastin metabolic process / glandular epithelial cell maturation / hypoxia-inducible factor-asparagine dioxygenase / : / regulation of transforming growth factor beta2 production ...epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / positive regulation of chemokine-mediated signaling pathway / hypoxia-inducible factor-1alpha signaling pathway / elastin metabolic process / glandular epithelial cell maturation / hypoxia-inducible factor-asparagine dioxygenase / : / regulation of transforming growth factor beta2 production / [protein]-asparagine 3-dioxygenase activity / connective tissue replacement involved in inflammatory response wound healing / peptidyl-histidine dioxygenase activity / cardiac ventricle morphogenesis / negative regulation of mesenchymal cell apoptotic process / hemoglobin biosynthetic process / peptidyl-aspartic acid 3-dioxygenase activity / retina vasculature development in camera-type eye / positive regulation of hormone biosynthetic process / mesenchymal cell apoptotic process / collagen metabolic process / positive regulation of mitophagy / Cellular response to hypoxia / intestinal epithelial cell maturation / negative regulation of growth / regulation of protein neddylation / negative regulation of bone mineralization / PTK6 Expression / lactate metabolic process / intracellular oxygen homeostasis / carboxylic acid binding / B-1 B cell homeostasis / positive regulation of vasculogenesis / vascular endothelial growth factor production / negative regulation of TOR signaling / ankyrin repeat binding / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / transcription regulator activator activity / dopaminergic neuron differentiation / STAT3 nuclear events downstream of ALK signaling / positive regulation of cytokine production involved in inflammatory response / oxygen sensor activity / motile cilium / negative regulation of thymocyte apoptotic process / positive regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of signaling receptor activity / Notch binding / insulin secretion involved in cellular response to glucose stimulus / response to iron ion / response to muscle activity / neural crest cell migration / embryonic hemopoiesis / Regulation of gene expression by Hypoxia-inducible Factor / regulation of glycolytic process / muscle cell cellular homeostasis / PTK6 promotes HIF1A stabilization / regulation of aerobic respiration / digestive tract morphogenesis / DNA-binding transcription repressor activity / DNA-binding transcription activator activity / positive regulation of neuroblast proliferation / axonal transport of mitochondrion / positive regulation of epithelial cell migration / heart looping / negative regulation of Notch signaling pathway / bone mineralization / TOR signaling / E-box binding / outflow tract morphogenesis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / intracellular glucose homeostasis / neuroblast proliferation / NF-kappaB binding / positive regulation of vascular endothelial growth factor production / epithelial to mesenchymal transition / negative regulation of reactive oxygen species metabolic process / embryonic placenta development / positive regulation of blood vessel endothelial cell migration / positive regulation of myoblast differentiation / cellular response to interleukin-1 / chondrocyte differentiation / cis-regulatory region sequence-specific DNA binding / axon cytoplasm / positive regulation of chemokine production / lactation / positive regulation of endothelial cell proliferation / positive regulation of glycolytic process / response to reactive oxygen species / negative regulation of miRNA transcription / positive regulation of erythrocyte differentiation / positive regulation of nitric-oxide synthase activity / nuclear receptor binding / ferrous iron binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Hsp90 protein binding / euchromatin / visual learning / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / transcription coactivator binding / cerebral cortex development
Similarity search - Function
Hypoxia-inducible factor-1 alpha / Clavaminate synthase-like / Hypoxia-inducible factor 1-alpha inhibitor, domain II / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / PAS fold-3 / Cupin-like domain 8 / Cupin-like domain ...Hypoxia-inducible factor-1 alpha / Clavaminate synthase-like / Hypoxia-inducible factor 1-alpha inhibitor, domain II / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / PAS fold-3 / Cupin-like domain 8 / Cupin-like domain / PAS fold / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / A domain family that is part of the cupin metalloenzyme superfamily. / Jelly Rolls / JmjC domain / JmjC domain profile. / 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 / RmlC-like jelly roll fold / PAS domain superfamily / Helix Hairpins / Jelly Rolls / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
2-OXOGLUTARIC ACID / BICARBONATE ION / : / Hypoxia-inducible factor 1-alpha / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / ISOMORPHOUS WITH 1H2N / Resolution: 2.3 Å
AuthorsMcdonough, M.A. / Schofield, C.J.
Citation
Journal: J.Biol.Chem. / Year: 2008
Title: Evidence that two enzyme-derived histidine ligands are sufficient for iron binding and catalysis by factor inhibiting HIF (FIH).
Authors: Hewitson, K.S. / Holmes, S.L. / Ehrismann, D. / Hardy, A.P. / Chowdhury, R. / Schofield, C.J. / McDonough, M.A.
#1: Journal: J.Biol.Chem. / Year: 2003
Title: Structure of Factor-Inhibiting Hypoxia-Inducible Factor (Hif) Reveals Mechanism of Oxidative Modification of Hif-1 Alpha
Authors: Elkins, J.M. / Hewitson, K.S. / Mcneill, L.A. / Seibel, J.F. / Schlemminger, I. / Pugh, C.W. / Ratcliffe, P.J. / Schofield, C.J.
#2: Journal: J.Am.Chem.Soc. / Year: 2005
Title: Selective inhibition of Factor Inhibiting Hypoxia inducible factor
Authors: McDonough, M.A. / McNeill, L.A. / Tilliet, M. / Papamicael, C.A. / Chen, Q.Y. / Banerji, B. / Hewitson, K.S. / Schofield, C.J.
History
DepositionOct 3, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.3Aug 30, 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: Hypoxia-inducible factor 1 alpha inhibitor
S: Hypoxia-inducible factor 1 alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,52310
Polymers44,7912
Non-polymers7318
Water3,153175
1
A: Hypoxia-inducible factor 1 alpha inhibitor
S: Hypoxia-inducible factor 1 alpha
hetero molecules

A: Hypoxia-inducible factor 1 alpha inhibitor
S: Hypoxia-inducible factor 1 alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,04520
Polymers89,5824
Non-polymers1,46316
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area7940 Å2
ΔGint-110 kcal/mol
Surface area29650 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)86.531, 86.531, 147.640
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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Hypoxia-inducible factor 1 ... , 2 types, 2 molecules AS

#1: Protein Hypoxia-inducible factor 1 alpha inhibitor / Hypoxia-inducible factor asparagine hydroxylase / Factor inhibiting HIF-1 / FIH-1


Mass: 40284.273 Da / Num. of mol.: 1 / Mutation: D201A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIF1AN / Plasmid: PET28A(+) / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q9NWT6, peptide-aspartate beta-dioxygenase
#2: Protein/peptide Hypoxia-inducible factor 1 alpha / HIF-1 alpha / HIF1 alpha / ARNT- interacting protein / Member of PAS protein 1 / MOP1


Mass: 4506.937 Da / Num. of mol.: 1 / Fragment: CTAD / Source method: obtained synthetically / Details: SYNTHETIC PEPTIDE FRAGMENT OF HIF-1 ALPHA / References: UniProt: Q16665

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Non-polymers , 6 types, 183 molecules

#3: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-BCT / BICARBONATE ION / Bicarbonate


Mass: 61.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CHO3 / Comment: pH buffer*YM
#6: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID / Α-Ketoglutaric acid


Mass: 146.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6O5
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 175 / 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: 3.08 Å3/Da / Density % sol: 63 %
Description: REJECTION CRITERIA AS REJECTION PROBABILITY, REJECTION
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: 1.6M AMMONIUM SULPHATE, 6% PEG400, 0.1M HEPES PH7.5 ARGON ATMOSPHERE, 14MG/ML PROTEIN WITH 1MM FE(II)SO4, 1MM ALPHA-KETOGLUTARATE, 1MM HIF-1ALPHA PEPTIDE, VAPOR DIFFUSION, HANGING DROP, ...Details: 1.6M AMMONIUM SULPHATE, 6% PEG400, 0.1M HEPES PH7.5 ARGON ATMOSPHERE, 14MG/ML PROTEIN WITH 1MM FE(II)SO4, 1MM ALPHA-KETOGLUTARATE, 1MM HIF-1ALPHA PEPTIDE, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 298.0K, pH 7.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM14 / Wavelength: 0.95372 / Wavelength: 0.95372 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 21, 2004 / Details: BENT + TOROIDAL
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95372 Å / Relative weight: 1
ReflectionResolution: 2.3→43.27 Å / Num. obs: 25664 / % possible obs: 99.8 % / Redundancy: 11.4 % / Biso Wilson estimate: 32.3 Å2 / Rmerge(I) obs: 0.067 / Rsym value: 0.029 / Net I/σ(I): 21.2
Reflection shellResolution: 2.3→2.35 Å / Redundancy: 11 % / Rmerge(I) obs: 0.4654 / Mean I/σ(I) obs: 2.18 / Rsym value: 0.3925 / % possible all: 97.1

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNS1.1phasing
RefinementMethod to determine structure: ISOMORPHOUS WITH 1H2N
Starting model: 1H2N

1h2n


Resolution: 2.3→43.27 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 190630.8 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: BULK SOLVENT MODEL USED. The bicarbonate ion is a provisional assignment based on observed electron density. This molecule was not confirmed as being present in the crystallization solution.
RfactorNum. reflection% reflectionSelection details
Rfree0.267 2410 9.9 %RANDOM
Rwork0.209 ---
obs0.209 24359 94.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 109.367 Å2 / ksol: 0.367653 e/Å3
Displacement parametersBiso mean: 59.2 Å2
Baniso -1Baniso -2Baniso -3
1--3.71 Å20 Å20 Å2
2---3.71 Å20 Å2
3---7.43 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.43 Å0.33 Å
Refinement stepCycle: LAST / Resolution: 2.3→43.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2692 0 43 175 2910
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d24.2
X-RAY DIFFRACTIONc_improper_angle_d0.96
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.021 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.395 345 9.7 %
Rwork0.346 3208 -
obs--84.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2gol.pargol.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION52og.par2og.top
X-RAY DIFFRACTION6bct.parbct.top

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