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- PDB-3hqu: PHD2:Fe:UN9:partial HIF1-alpha substrate complex -

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Basic information

Entry
Database: PDB / ID: 3hqu
TitlePHD2:Fe:UN9:partial HIF1-alpha substrate complex
Components
  • Egl nine homolog 1
  • Hypoxia-inducible factor 1 alpha
KeywordsOXIDOREDUCTASE/TRANSCRIPTION / double stranded beta-helix / Alternative splicing / Congenital erythrocytosis / Dioxygenase / Disease mutation / Iron / Metal-binding / Oxidoreductase / Vitamin C / Zinc / Zinc-finger / Activator / Cytoplasm / DNA-binding / Hydroxylation / Isopeptide bond / Nucleus / Phosphoprotein / Polymorphism / S-nitrosylation / Transcription / Transcription regulation / Ubl conjugation / OXIDOREDUCTASE-TRANSCRIPTION COMPLEX
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 / glandular epithelial cell maturation / positive regulation of chemokine-mediated signaling pathway / elastin metabolic process / peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase ...epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / hypoxia-inducible factor-1alpha signaling pathway / glandular epithelial cell maturation / positive regulation of chemokine-mediated signaling pathway / elastin metabolic process / peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / regulation of transforming growth factor beta2 production / peptidyl-proline dioxygenase activity / connective tissue replacement involved in inflammatory response wound healing / negative regulation of cyclic-nucleotide phosphodiesterase activity / hemoglobin biosynthetic process / negative regulation of mesenchymal cell apoptotic process / cardiac ventricle morphogenesis / positive regulation of hormone biosynthetic process / retina vasculature development in camera-type eye / intestinal epithelial cell maturation / Cellular response to hypoxia / negative regulation of growth / regulation protein catabolic process at postsynapse / mesenchymal cell apoptotic process / positive regulation of mitophagy / regulation of protein neddylation / PTK6 Expression / negative regulation of bone mineralization / intracellular oxygen homeostasis / collagen metabolic process / B-1 B cell homeostasis / vascular endothelial growth factor production / labyrinthine layer development / cardiac muscle tissue morphogenesis / dopaminergic neuron differentiation / transcription regulator activator activity / heart trabecula formation / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / lactate metabolic process / regulation of modification of postsynaptic structure / STAT3 nuclear events downstream of ALK signaling / 2-oxoglutarate-dependent dioxygenase activity / positive regulation of cytokine production involved in inflammatory response / negative regulation of thymocyte apoptotic process / motile cilium / positive regulation of vascular endothelial growth factor receptor signaling pathway / negative regulation of TOR signaling / L-ascorbic acid binding / positive regulation of signaling receptor activity / insulin secretion involved in cellular response to glucose stimulus / response to iron ion / response to muscle activity / neural crest cell migration / regulation of glycolytic process / Regulation of gene expression by Hypoxia-inducible Factor / embryonic hemopoiesis / DNA-binding transcription activator activity / DNA-binding transcription repressor activity / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / response to nitric oxide / regulation of aerobic respiration / ventricular septum morphogenesis / muscle cell cellular homeostasis / positive regulation of neuroblast proliferation / positive regulation of epithelial cell migration / axonal transport of mitochondrion / bone mineralization / heart looping / E-box binding / intracellular glucose homeostasis / outflow tract morphogenesis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / cellular response to interleukin-1 / positive regulation of vascular endothelial growth factor production / neuroblast proliferation / negative regulation of reactive oxygen species metabolic process / positive regulation of blood vessel endothelial cell migration / embryonic placenta development / TOR signaling / epithelial to mesenchymal transition / cis-regulatory region sequence-specific DNA binding / regulation of angiogenesis / chondrocyte differentiation / positive regulation of chemokine production / axon cytoplasm / positive regulation of endothelial cell proliferation / lactation / positive regulation of glycolytic process / positive regulation of erythrocyte differentiation / negative regulation of miRNA transcription / positive regulation of nitric-oxide synthase activity / response to reactive oxygen species / nuclear receptor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Hsp90 protein binding / ferrous iron binding / visual learning / euchromatin / negative regulation of DNA-binding transcription factor activity
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, alpha subunit-like / Hypoxia-inducible factor-1 / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / PAS fold-3 / Prolyl 4-hydroxylase, alpha subunit ...Hypoxia-inducible factor-1 alpha / : / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / PAS fold-3 / Prolyl 4-hydroxylase, alpha subunit / Prolyl 4-hydroxylase alpha subunit homologues. / q2cbj1_9rhob like domain / PAS fold / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Oxoglutarate/iron-dependent dioxygenase / Fe(2+) 2-oxoglutarate dioxygenase domain profile. / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural 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 / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
: / Chem-UN9 / Hypoxia-inducible factor 1-alpha / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 Å
AuthorsChowdhury, R. / McDonough, M.A. / Schofield, C.J.
Citation
Journal: Structure / Year: 2009
Title: Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases
Authors: Chowdhury, R. / McDonough, M.A. / Mecinovic, J. / Loenarz, C. / Flashman, E. / Hewitson, K.S. / Domene, C. / Schofield, C.J.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2006
Title: Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)
Authors: McDonough, M.A. / Li, V. / Flashman, E. / Chowdhury, R. / Mohr, C. / Lienard, B.M.R. / Zondlo, J. / Oldham, N.J. / Clifton, I.J. / Lewis, J. / McNeill, L.A. / Kurzeja, R.J.M. / Hewitson, K.S. ...Authors: McDonough, M.A. / Li, V. / Flashman, E. / Chowdhury, R. / Mohr, C. / Lienard, B.M.R. / Zondlo, J. / Oldham, N.J. / Clifton, I.J. / Lewis, J. / McNeill, L.A. / Kurzeja, R.J.M. / Hewitson, K.S. / Yang, E. / Jordan, S. / Syed, R.S. / Schofield, C.J.
History
DepositionJun 8, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 28, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Egl nine homolog 1
S: Hypoxia-inducible factor 1 alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,8884
Polymers29,5522
Non-polymers3372
Water2,432135
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)110.819, 110.819, 39.615
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63

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Components

#1: Protein Egl nine homolog 1 / Prolyl hydroxylase / Hypoxia-inducible factor prolyl hydroxylase 2 / HIF-prolyl hydroxylase 2 / HIF- ...Prolyl hydroxylase / Hypoxia-inducible factor prolyl hydroxylase 2 / HIF-prolyl hydroxylase 2 / HIF-PH2 / HPH-2 / Prolyl hydroxylase domain-containing protein 2 / PHD2 / SM-20


Mass: 27525.314 Da / Num. of mol.: 1 / Fragment: PHD2 catalytic domain, residues 181-426
Source method: isolated from a genetically manipulated source
Details: HIS-tag cleaved with thrombin after Ni+ affinity purification followed by gel filtration
Source: (gene. exp.) Homo sapiens (human) / Gene: PHD2(amino acids 181-426) / Plasmid: pET28a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q9GZT9, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor
#2: Protein/peptide Hypoxia-inducible factor 1 alpha / HIF-1 alpha / HIF1 alpha / ARNT-interacting protein / Member of PAS protein 1 / Basic-helix-loop- ...HIF-1 alpha / HIF1 alpha / ARNT-interacting protein / Member of PAS protein 1 / Basic-helix-loop-helix-PAS protein MOP1


Mass: 2026.287 Da / Num. of mol.: 1 / Fragment: C-terminal degradation domain, residues 558-574 / Source method: obtained synthetically / Details: peptide synthesis (HYP564) / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16665
#3: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe
#4: Chemical ChemComp-UN9 / N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)CARBONYL]GLYCINE


Mass: 280.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H9ClN2O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / 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: 2.38 Å3/Da / Density % sol: 48.24 % / Mosaicity: 0.34 °
Crystal growTemperature: 298 K / Method: hanging drop / pH: 6.5
Details: 1.6M AMMONIUM SULFATE, 4% DIOXANE, 0.1M MES PH6.5, ARGON ATMOSPHERE, 20MG/ML PROTEIN WITH 1MM FE(II)SO4, 10MM HIF1A-CODD-OH PEPTIDE, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX10.1 / Wavelength: 1.29 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 8, 2005
Details: Rh coated collimating mirror, a double crystal Si(III) monochromator with horizontal saggital focusing system, and finally a second Rh coated mirror for vertical focusing.
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.29 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 12581 / % possible obs: 99.1 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.2 % / Biso Wilson estimate: 33.7 Å2 / Rmerge(I) obs: 0.068 / Χ2: 0.998 / Net I/σ(I): 16.658
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.312 / Mean I/σ(I) obs: 3.3 / Num. unique all: 1193 / Χ2: 0.962 / % possible all: 96.2

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNS1.1refinement
PDB_EXTRACT3.005data extraction
MAR345dtbdata collection
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 2G19

2g19


Resolution: 2.3→30.55 Å / Rfactor Rfree error: 0.006 / Occupancy max: 1 / Occupancy min: 0.5 / Data cutoff high absF: 195390 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.222 1259 10.5 %RANDOM
Rwork0.188 ---
obs-12030 95.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 58.515 Å2 / ksol: 0.363 e/Å3
Displacement parametersBiso max: 74.08 Å2 / Biso mean: 33.683 Å2 / Biso min: 1.07 Å2
Baniso -1Baniso -2Baniso -3
1--0.74 Å21.66 Å20 Å2
2---0.74 Å20 Å2
3---1.48 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.24 Å
Refinement stepCycle: LAST / Resolution: 2.3→30.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1753 0 20 135 1908
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d24.9
X-RAY DIFFRACTIONc_improper_angle_d0.84
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.022 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.299 183 9.9 %
Rwork0.235 1665 -
all-1848 -
obs--89.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4fg2216.paramfg2216.top

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