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- PDB-5l9b: HIF PROLYL HYDROXYLASE 2 (PHD2/ EGLN1) IN COMPLEX WITH 2-OXOGLUTA... -

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Basic information

Entry
Database: PDB / ID: 5l9b
TitleHIF PROLYL HYDROXYLASE 2 (PHD2/ EGLN1) IN COMPLEX WITH 2-OXOGLUTARATE (2OG) AND HIF-1ALPHA CODD (556-574)
Components
  • Egl nine homolog 1
  • Hypoxia-inducible factor 1-alpha
KeywordsOXIDOREDUCTASE / NON-HEME DIOXYGENASE / IRON / 2-OXOGLUTARATE / HYPOXIA-INDUCIBLE FACTOR / HIF / HIF PROLYL HYDROXYLASE DOMAIN 2 / PHD2 / EGLN1 / OXYGENASE / HYPOXIA / DNA-BINDING / METAL-BINDING / TRANSCRIPTION / HELIX-LOOP-HELIX-BETA / DSBH / FACIAL TRIAD / CYTOPLASM / TRANSCRIPTION/EPIGENETIC REGULATION / SIGNALING / DEVELOPMENT / CELL STRUCTURE / BETA-HYDROXYLATION / TRANSCRIPTION ACTIVATOR/INHIBITOR / UBL CONJUGATION / POLYMORPHISM / VITAMIN C / ZINC-FINGER / FAMILIAL ERYTHROCYTOSIS / BREAST CANCER / TRANSCRIPTION COMPLEX
Function / homology
Function and homology information


elastin metabolic process / positive regulation of chemokine-mediated signaling pathway / regulation of transforming growth factor beta2 production / negative regulation of hypoxia-inducible factor-1alpha signaling pathway / peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / hypoxia-inducible factor-proline dioxygenase activity / connective tissue replacement involved in inflammatory response wound healing / peptidyl-proline dioxygenase activity / positive regulation of hormone biosynthetic process ...elastin metabolic process / positive regulation of chemokine-mediated signaling pathway / regulation of transforming growth factor beta2 production / negative regulation of hypoxia-inducible factor-1alpha signaling pathway / peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / hypoxia-inducible factor-proline dioxygenase activity / connective tissue replacement involved in inflammatory response wound healing / peptidyl-proline dioxygenase activity / positive regulation of hormone biosynthetic process / Cellular response to hypoxia / collagen metabolic process / PTK6 Expression / regulation protein catabolic process at postsynapse / regulation of protein neddylation / vascular endothelial growth factor production / intracellular oxygen homeostasis / negative regulation of ossification / transcription regulator activator activity / regulation of modification of postsynaptic structure / STAT3 nuclear events downstream of ALK signaling / 2-oxoglutarate-dependent dioxygenase activity / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / motile cilium / L-ascorbic acid binding / positive regulation of vascular endothelial growth factor receptor signaling pathway / Regulation of gene expression by Hypoxia-inducible Factor / response to iron ion / positive regulation of cytokine production involved in inflammatory response / regulation of glycolytic process / DNA-binding transcription repressor activity / response to nitric oxide / PTK6 promotes HIF1A stabilization / DNA-binding transcription activator activity / axonal transport of mitochondrion / E-box binding / positive regulation of epithelial cell migration / cellular response to interleukin-1 / epithelial to mesenchymal transition / regulation of angiogenesis / positive regulation of vascular endothelial growth factor production / positive regulation of blood vessel endothelial cell migration / cis-regulatory region sequence-specific DNA binding / positive regulation of chemokine production / negative regulation of reactive oxygen species biosynthetic process / positive regulation of endothelial cell proliferation / positive regulation of erythrocyte differentiation / axon cytoplasm / negative regulation of miRNA transcription / regulation of neuron apoptotic process / positive regulation of glycolytic process / intracellular glucose homeostasis / nuclear receptor binding / transcription corepressor binding / enzyme inhibitor activity / response to reactive oxygen species / RNA polymerase II transcription regulatory region sequence-specific DNA binding / RNA polymerase II transcription regulator complex / cellular response to virus / euchromatin / Hsp90 protein binding / ferrous iron binding / positive regulation of miRNA transcription / NOTCH1 Intracellular Domain Regulates Transcription / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / transcription coactivator binding / histone deacetylase binding / positive regulation of angiogenesis / p53 binding / regulation of gene expression / Regulation of PD-L1(CD274) transcription / transcription regulator complex / Neddylation / Interleukin-4 and Interleukin-13 signaling / cellular response to oxidative stress / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to hypoxia / response to hypoxia / RNA polymerase II-specific DNA-binding transcription factor binding / nuclear body / intracellular iron ion homeostasis / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / postsynaptic density / Ub-specific processing proteases / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein heterodimerization activity / negative regulation of gene expression / protein domain specific binding / ubiquitin protein ligase binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / protein kinase binding / positive regulation of DNA-templated transcription / chromatin / glutamatergic synapse / enzyme binding / signal transduction
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 / PAS fold-3 / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily ...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 / PAS fold-3 / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / PAS fold / Prolyl 4-hydroxylase, alpha subunit / Prolyl 4-hydroxylase alpha subunit homologues. / MYND finger / q2cbj1_9rhob like domain / Zinc finger MYND-type signature. / Zinc finger, MYND-type / 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
2-OXOGLUTARIC ACID / : / Hypoxia-inducible factor 1-alpha / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsChowdhury, R. / Schofield, C.J.
Citation
Journal: Nat Commun / Year: 2016
Title: Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases.
Authors: Chowdhury, R. / Leung, I.K. / Tian, Y.M. / Abboud, M.I. / Ge, W. / Domene, C. / Cantrelle, F.X. / Landrieu, I. / Hardy, A.P. / Pugh, C.W. / Ratcliffe, P.J. / Claridge, T.D. / Schofield, C.J.
#1: 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.
#2: Journal: ACS Chem. Biol. / Year: 2013
Title: Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases.
Authors: Chowdhury, R. / Candela-Lena, J.I. / Chan, M.C. / Greenald, D.J. / Yeoh, K.K. / Tian, Y.M. / McDonough, M.A. / Tumber, A. / Rose, N.R. / Conejo-Garcia, A. / Demetriades, M. / Mathavan, S. / ...Authors: Chowdhury, R. / Candela-Lena, J.I. / Chan, M.C. / Greenald, D.J. / Yeoh, K.K. / Tian, Y.M. / McDonough, M.A. / Tumber, A. / Rose, N.R. / Conejo-Garcia, A. / Demetriades, M. / Mathavan, S. / Kawamura, A. / Lee, M.K. / van Eeden, F. / Pugh, C.W. / Ratcliffe, P.J. / Schofield, C.J.
History
DepositionJun 10, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 31, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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
B: Egl nine homolog 1
C: Hypoxia-inducible factor 1-alpha
D: Hypoxia-inducible factor 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,8698
Polymers60,4674
Non-polymers4024
Water5,368298
1
A: Egl nine homolog 1
C: Hypoxia-inducible factor 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,4344
Polymers30,2332
Non-polymers2012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2900 Å2
ΔGint-16 kcal/mol
Surface area10920 Å2
MethodPISA
2
B: Egl nine homolog 1
D: Hypoxia-inducible factor 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,4344
Polymers30,2332
Non-polymers2012
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2990 Å2
ΔGint-19 kcal/mol
Surface area10630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.193, 76.395, 70.962
Angle α, β, γ (deg.)90.00, 90.03, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 27978.762 Da / Num. of mol.: 2 / Fragment: UNP residues 181-426 / Mutation: C201A, R398A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGLN1, C1orf12, PNAS-118, PNAS-137 / Plasmid: PET28A(+) / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9GZT9, hypoxia-inducible factor-proline dioxygenase
#2: Protein/peptide Hypoxia-inducible factor 1-alpha / HIF1-alpha / ARNT-interacting protein / Basic-helix-loop-helix-PAS protein MOP1 / Class E basic ...HIF1-alpha / ARNT-interacting protein / Basic-helix-loop-helix-PAS protein MOP1 / Class E basic helix-loop-helix protein 78 / bHLHe78 / Member of PAS protein 1 / PAS domain-containing protein 8


Mass: 2254.532 Da / Num. of mol.: 2 / Fragment: UNP residues 556-574 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16665
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID


Mass: 146.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H6O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 298 / 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: 2.04 Å3/Da / Density % sol: 39.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.2 M Magnesium chloride hexahydrate, 0.1 M BIS-TRIS pH 5.5, 25% w/v polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 19, 2016 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
Reflection twinOperator: h,-k,-l / Fraction: 0.438
ReflectionResolution: 1.95→40.193 Å / Num. obs: 31425 / % possible obs: 99.1 % / Redundancy: 4.8 % / Biso Wilson estimate: 20.51 Å2 / Rmerge(I) obs: 0.167 / Net I/σ(I): 8.6543
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.9 / Mean I/σ(I) obs: 1.713 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
HKL-2000706edata reduction
HKL-2000706edata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HQR

3hqr


Resolution: 1.95→40.193 Å / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.48 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflectionSelection details
Rfree0.1865 1609 5.18 %RANDOM
Rwork0.1573 ---
obs0.1607 31079 99.06 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.788 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso mean: 25 Å2
Baniso -1Baniso -2Baniso -3
1-6.2684 Å20 Å20.7557 Å2
2---6.1545 Å20 Å2
3----0.1139 Å2
Refinement stepCycle: LAST / Resolution: 1.95→40.193 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3667 0 22 298 3987
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033769
X-RAY DIFFRACTIONf_angle_d0.615111
X-RAY DIFFRACTIONf_dihedral_angle_d12.852221
X-RAY DIFFRACTIONf_chiral_restr0.045550
X-RAY DIFFRACTIONf_plane_restr0.004672
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9519-2.01460.26491420.23272645X-RAY DIFFRACTION93
2.0146-2.08630.25191160.21992644X-RAY DIFFRACTION94
2.0863-2.16950.23691260.2022638X-RAY DIFFRACTION94
2.1695-2.26770.23671340.19112667X-RAY DIFFRACTION94
2.2677-2.38660.22881160.17852679X-RAY DIFFRACTION95
2.3866-2.53510.22531360.16492681X-RAY DIFFRACTION95
2.5351-2.72910.21021760.16632628X-RAY DIFFRACTION93
2.7291-3.00060.16461950.14492601X-RAY DIFFRACTION92
3.0006-3.42760.17771130.13052709X-RAY DIFFRACTION96
3.4276-4.29190.15861680.12032686X-RAY DIFFRACTION94
4.2919-12.89920.15191790.14472694X-RAY DIFFRACTION93

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