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- PDB-5la9: HIF prolyl hydroxylase 2 (PHD2-R281C/V314C) cross-linked to HIF-1... -

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Basic information

Entry
Database: PDB / ID: 5la9
TitleHIF prolyl hydroxylase 2 (PHD2-R281C/V314C) cross-linked to HIF-1alpha NODD-L397C/D412C and N-oxalylglycine (NOG) (complex-2)
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


epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / intestinal epithelial cell maturation / : / 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 ...epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / intestinal epithelial cell maturation / : / 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 / peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / negative regulation of hypoxia-inducible factor-1alpha signaling pathway / peptidyl-proline dioxygenase activity / hemoglobin biosynthetic process / negative regulation of mesenchymal cell apoptotic process / cardiac ventricle morphogenesis / connective tissue replacement involved in inflammatory response wound healing / negative regulation of growth / positive regulation of hormone biosynthetic process / Cellular response to hypoxia / retina vasculature development in camera-type eye / mesenchymal cell apoptotic process / regulation of protein neddylation / regulation protein catabolic process at postsynapse / PTK6 Expression / negative regulation of bone mineralization / intracellular oxygen homeostasis / B-1 B cell homeostasis / collagen metabolic process / vascular endothelial growth factor production / regulation of modification of postsynaptic structure / labyrinthine layer development / dopaminergic neuron differentiation / 2-oxoglutarate-dependent dioxygenase activity / transcription regulator activator activity / heart trabecula formation / cardiac muscle tissue morphogenesis / STAT3 nuclear events downstream of ALK signaling / lactate metabolic process / negative regulation of thymocyte apoptotic process / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / positive regulation of cytokine production involved in inflammatory response / L-ascorbic acid binding / 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 / Regulation of gene expression by Hypoxia-inducible Factor / neural crest cell migration / embryonic hemopoiesis / regulation of glycolytic process / motile cilium / DNA-binding transcription repressor activity / response to nitric oxide / PTK6 promotes HIF1A stabilization / DNA-binding transcription activator activity / muscle cell cellular homeostasis / ventricular septum morphogenesis / positive regulation of neuroblast proliferation / digestive tract morphogenesis / response to muscle activity / axonal transport of mitochondrion / heart looping / bone mineralization / intracellular glucose homeostasis / E-box binding / TOR signaling / outflow tract morphogenesis / positive regulation of vascular endothelial growth factor production / positive regulation of macroautophagy / positive regulation of epithelial cell migration / epithelial to mesenchymal transition / cellular response to interleukin-1 / positive regulation of blood vessel endothelial cell migration / neuroblast proliferation / enzyme inhibitor activity / regulation of angiogenesis / chondrocyte differentiation / embryonic placenta development / positive regulation of insulin secretion involved in cellular response to glucose stimulus / cis-regulatory region sequence-specific DNA binding / positive regulation of chemokine production / regulation of neuron apoptotic process / lactation / positive regulation of endothelial cell proliferation / axon cytoplasm / negative regulation of miRNA transcription / positive regulation of erythrocyte differentiation / positive regulation of glycolytic process / nuclear receptor binding / transcription corepressor binding / response to reactive oxygen species / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Hsp90 protein binding / ferrous iron binding / euchromatin / cerebral cortex development / visual learning
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 / Zinc finger MYND-type signature. / Zinc finger, MYND-type / Zinc finger MYND-type profile. / q2cbj1_9rhob like domain / 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
: / N-OXALYLGLYCINE / Hypoxia-inducible factor 1-alpha / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.813 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 14, 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 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)60,1489
Polymers59,6484
Non-polymers5005
Water1,33374
1
A: Egl nine homolog 1
C: Hypoxia-inducible factor 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1225
Polymers29,8242
Non-polymers2983
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-40 kcal/mol
Surface area9820 Å2
MethodPISA
2
B: Egl nine homolog 1
D: Hypoxia-inducible factor 1-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,0264
Polymers29,8242
Non-polymers2022
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2850 Å2
ΔGint-30 kcal/mol
Surface area10420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.467, 97.329, 71.001
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#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: 27928.723 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN UNP residues 181-426 / Mutation: C201A, R281C, V314C, 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: 1895.203 Da / Num. of mol.: 2
Fragment: N-TERMINAL OXYGEN DEPENDENT DEGRADATION DOMAIN (NODD), UNP residues 395-413
Mutation: L397C, D412C / Source method: obtained synthetically / Details: Synthetic Peptide / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16665

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Non-polymers , 4 types, 79 molecules

#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-OGA / N-OXALYLGLYCINE


Mass: 147.086 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H5NO5
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 3.04 Å3/Da / Density % sol: 59.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M HEPES pH 7.5, 2.0 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 4, 2011 / 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
ReflectionResolution: 2.81→48.129 Å / Num. obs: 15152 / % possible obs: 98.5 % / Redundancy: 3.4 % / Biso Wilson estimate: 38 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.245 / Net I/σ(I): 4.7769
Reflection shellResolution: 2.81→2.9 Å / Redundancy: 3.5 % / Rmerge(I) obs: 1.25 / Mean I/σ(I) obs: 1.7378 / % possible all: 99.3

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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: 2.813→48.129 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2785 717 4.75 %RANDOM
Rwork0.2513 ---
obs0.2525 15094 97.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 56.9 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 37.7 Å2
Baniso -1Baniso -2Baniso -3
1-19.42 Å20 Å20 Å2
2---4.43 Å20 Å2
3----14.98 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.49 Å0.42 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.64 Å
Refinement stepCycle: LAST / Resolution: 2.813→48.129 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3429 0 27 74 3530
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033532
X-RAY DIFFRACTIONf_angle_d0.6124799
X-RAY DIFFRACTIONf_dihedral_angle_d15.1752065
X-RAY DIFFRACTIONf_chiral_restr0.044523
X-RAY DIFFRACTIONf_plane_restr0.004630
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8132-3.03040.37071270.33212762X-RAY DIFFRACTION96
3.0304-3.33530.36521490.2992890X-RAY DIFFRACTION99
3.3353-3.81770.28741530.2582853X-RAY DIFFRACTION98
3.8177-4.80920.23751440.21852806X-RAY DIFFRACTION96
4.8092-48.1360.23431440.21943066X-RAY DIFFRACTION99

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