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- PDB-7q5x: HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH 2-OXOGLUTAR... -

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Basic information

Entry
Database: PDB / ID: 7q5x
TitleHIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH 2-OXOGLUTARATE (2OG) AND HIF-2 ALPHA CODD (523-542)
Components
  • Egl nine homolog 1
  • Endothelial PAS domain-containing protein 1
KeywordsOXIDOREDUCTASE / PHD2 / HIF-2Alpha / Complex / 2OG / Hypoxia
Function / homology
Function and homology information


myoblast fate commitment / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / peptidyl-proline 4-dioxygenase activity / peptidyl-proline dioxygenase activity / peptidyl-proline hydroxylation to 4-hydroxy-L-proline / negative regulation of cyclic-nucleotide phosphodiesterase activity / regulation protein catabolic process at postsynapse / Cellular response to hypoxia / regulation of protein neddylation ...myoblast fate commitment / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / peptidyl-proline 4-dioxygenase activity / peptidyl-proline dioxygenase activity / peptidyl-proline hydroxylation to 4-hydroxy-L-proline / negative regulation of cyclic-nucleotide phosphodiesterase activity / regulation protein catabolic process at postsynapse / Cellular response to hypoxia / regulation of protein neddylation / Transcriptional regulation of pluripotent stem cells / PTK6 Expression / intracellular oxygen homeostasis / labyrinthine layer development / 2-oxoglutarate-dependent dioxygenase activity / norepinephrine metabolic process / cardiac muscle tissue morphogenesis / heart trabecula formation / regulation of modification of postsynaptic structure / surfactant homeostasis / epithelial cell maturation / L-ascorbic acid binding / Regulation of gene expression by Hypoxia-inducible Factor / response to nitric oxide / ventricular septum morphogenesis / embryonic placenta development / blood vessel remodeling / regulation of angiogenesis / Pexophagy / visual perception / regulation of heart rate / mitochondrion organization / erythrocyte differentiation / ferrous iron binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / lung development / mRNA transcription by RNA polymerase II / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / multicellular organismal-level iron ion homeostasis / Neddylation / positive regulation of cold-induced thermogenesis / cellular response to hypoxia / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / response to oxidative stress / intracellular iron ion homeostasis / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / postsynaptic density / response to hypoxia / DNA-binding transcription factor activity, RNA polymerase II-specific / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein heterodimerization activity / intracellular membrane-bounded organelle / glutamatergic synapse / chromatin / regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / Prolyl 4-hydroxylase, alpha subunit / Prolyl 4-hydroxylase alpha subunit homologues. / MYND finger ...HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / Prolyl 4-hydroxylase, alpha subunit / Prolyl 4-hydroxylase alpha subunit homologues. / 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) / PAS domain / 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 / PAS domain superfamily
Similarity search - Domain/homology
2-OXOGLUTARIC ACID / FORMIC ACID / : / DI(HYDROXYETHYL)ETHER / Endothelial PAS domain-containing protein 1 / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.21 Å
AuthorsFigg Jr, W.D. / McDonough, M.A. / Chowdhury, R. / Nakashima, Y. / Schofield, C.J.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Wellcome Trust106244/Z/14/Z United Kingdom
Cancer Research UK United Kingdom
CitationJournal: Proteins / Year: 2023
Title: Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2 alpha to prolyl hydroxylase domain 2.
Authors: Figg Jr., W.D. / Fiorini, G. / Chowdhury, R. / Nakashima, Y. / Tumber, A. / McDonough, M.A. / Schofield, C.J.
History
DepositionNov 4, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 31, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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: Endothelial PAS domain-containing protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,43123
Polymers28,3462
Non-polymers1,08521
Water2,648147
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5870 Å2
ΔGint-64 kcal/mol
Surface area10820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)130.454, 38.175, 42.751
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#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: 26036.582 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGLN1, C1orf12, PNAS-118, PNAS-137 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9GZT9, hypoxia-inducible factor-proline dioxygenase
#2: Protein/peptide Endothelial PAS domain-containing protein 1 / EPAS-1 / Basic-helix-loop-helix-PAS protein MOP2 / Class E basic helix-loop-helix protein 73 / ...EPAS-1 / Basic-helix-loop-helix-PAS protein MOP2 / Class E basic helix-loop-helix protein 73 / bHLHe73 / HIF-1-alpha-like factor / HLF / Hypoxia-inducible factor 2-alpha / HIF-2-alpha / HIF2-alpha / Member of PAS protein 2 / PAS domain-containing protein 2


Mass: 2309.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q99814

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Non-polymers , 8 types, 168 molecules

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


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-AKG / 2-OXOGLUTARIC ACID / Α-Ketoglutaric acid


Mass: 146.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H6O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: CH2O2
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#9: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 147 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 1.88 Å3/Da / Density % sol: 34.49 % / Description: Rod
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Sample: 1.0 mM PHD2, 1.2 mM MnCl2, 2.0 mM 2OG, 2 mM 3C, 2-4 mM HIF-2alpha-CODD; Reservoir: 0.33 M Magnesium formate (range: 0.25-0.39 M), 17.5% w/v polyethylene glycol 3350 (range: 18-22%); ...Details: Sample: 1.0 mM PHD2, 1.2 mM MnCl2, 2.0 mM 2OG, 2 mM 3C, 2-4 mM HIF-2alpha-CODD; Reservoir: 0.33 M Magnesium formate (range: 0.25-0.39 M), 17.5% w/v polyethylene glycol 3350 (range: 18-22%); Sitting drop (200 nl): protein-to-well ratio, 1:1; Cryo-protectant: 15% v/v dilution of reservior solution with glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.97962 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 7, 2019
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97962 Å / Relative weight: 1
ReflectionResolution: 1.21→43.48 Å / Num. obs: 66301 / % possible obs: 100 % / Redundancy: 12.2 % / Biso Wilson estimate: 14.13 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1317 / Rpim(I) all: 0.039 / Rrim(I) all: 0.138 / Net I/σ(I): 10
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) all% possible all
1.21-1.2310.44.204132600.4210.7771.54.89899.1
3.28-43.5111.531.336170.0180.061100

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.42 Å42.75 Å
Translation5.42 Å42.75 Å

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Processing

Software
NameVersionClassification
PHENIX1.19.1refinement
REFMAC5.5refinement
xia20.5.898data reduction
DIALS1.14.8data scaling
PHASER2.8.2phasing
Coot0.9.6model building
MolProbity4.5.1model building
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HQR

3hqr


Resolution: 1.21→42.75 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 17.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1759 3329 5.03 %
Rwork0.157 62868 -
obs0.158 66197 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.02 Å2 / Biso mean: 23.0209 Å2 / Biso min: 8.76 Å2
Refinement stepCycle: final / Resolution: 1.21→42.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1867 0 108 159 2134
Biso mean--44.31 33.45 -
Num. residues----240
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.21-1.230.31671430.3182562270599
1.23-1.250.30991430.303225592702100
1.25-1.260.30011250.285725912716100
1.26-1.290.26861360.256925862722100
1.29-1.310.25671260.249226152741100
1.31-1.330.22441340.227225792713100
1.33-1.360.241570.220225692726100
1.36-1.380.21571240.208425892713100
1.38-1.410.21741710.198925732744100
1.41-1.450.23231370.191625562693100
1.45-1.480.20211330.188826222755100
1.48-1.520.21591390.196926162755100
1.52-1.570.1921290.179625742703100
1.57-1.620.19361460.158926212767100
1.62-1.680.16991450.158625902735100
1.68-1.740.18041330.149826342767100
1.74-1.820.14891350.14226132748100
1.82-1.920.15541300.140726322762100
1.92-2.040.17031380.140326512789100
2.04-2.20.16161400.126526322772100
2.2-2.420.15811610.130726342795100
2.42-2.770.16161140.132826952809100
2.77-3.490.14321420.13227222864100
3.49-42.750.16861480.157728533001100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.898-0.77410.85761.9224-0.91291.0319-0.1169-0.16150.270.12810.0672-0.0433-0.1326-0.15720.04350.17930.0127-0.00810.0999-0.03280.18514.385824.832412.2461
21.4993-1.2938-1.6143.68433.52433.50180.0199-0.4058-0.06940.60710.0937-0.353-0.0059-0.0035-0.1250.31910.015-0.03760.1940.01790.119918.25676.479227.3292
31.7318-0.8048-0.27132.03260.49161.2517-0.0537-0.1223-0.13260.14120.04390.01110.1711-0.02110.01130.1251-0.0051-0.00870.07640.01690.124314.95283.3612.96
43.2598-0.63591.22332.9656-1.09892.316-0.01680.0850.0455-0.05220.05150.1737-0.0678-0.0683-0.08530.12030.00950.01040.0641-0.02420.089911.267210.99248.1272
52.3836-0.07090.71221.0586-0.02131.8976-0.0051-0.0579-0.05090.0456-0.0082-0.1264-0.0140.06780.00730.1194-0.0059-0.01490.04220.00330.125224.08559.445210.4149
63.39810.3278-1.61493.2361-5.17288.7397-0.0010.27610.5664-0.2152-0.0048-0.2069-0.20850.09160.0080.1641-0.01980.00610.090.01710.203228.196719.68211.3191
71.1575-0.08450.06511.2965-0.09411.82280.0091-0.02620.07390.01820.0123-0.1635-0.04940.0791-0.01910.1322-0.0054-0.01120.0691-0.00770.134424.277313.93759.1011
84.41650.99483.33461.19560.7014.1235-0.07280.2116-0.041-0.08840.03990.06240.108-0.0290.01230.1294-0.01390.0040.0794-0.00660.123710.33115.28213.0208
93.68772.6407-3.26295.4109-5.20475.40220.00091.0612-0.261-1.24020.1027-0.56110.85030.0171-0.10070.29180.0190.03970.2117-0.03430.218722.11641.4158-5.8872
105.1747-1.5757-2.70570.62130.6581.6328-0.30720.3417-0.8766-0.0095-0.05160.41040.2245-0.31940.26220.1734-0.02070.02980.1516-0.03190.29497.47972.25325.7695
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 187 through 215 )A187 - 215
2X-RAY DIFFRACTION2chain 'A' and (resid 216 through 231 )A216 - 231
3X-RAY DIFFRACTION3chain 'A' and (resid 232 through 283 )A232 - 283
4X-RAY DIFFRACTION4chain 'A' and (resid 284 through 304 )A284 - 304
5X-RAY DIFFRACTION5chain 'A' and (resid 305 through 342 )A305 - 342
6X-RAY DIFFRACTION6chain 'A' and (resid 343 through 353 )A343 - 353
7X-RAY DIFFRACTION7chain 'A' and (resid 354 through 381 )A354 - 381
8X-RAY DIFFRACTION8chain 'A' and (resid 382 through 407 )A382 - 407
9X-RAY DIFFRACTION9chain 'B' and (resid 524 through 528 )B524 - 528
10X-RAY DIFFRACTION10chain 'B' and (resid 529 through 542 )B529 - 542

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