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- PDB-5lbf: HIF prolyl hydroxylase 2 (PHD2/EGLN1) K293K/G294E variant in comp... -

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Basic information

Entry
Database: PDB / ID: 5lbf
TitleHIF prolyl hydroxylase 2 (PHD2/EGLN1) K293K/G294E variant in complex with Mn(II) and N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine (IOX3/FG2216)
ComponentsEgl nine homolog 1
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


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 / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / regulation of modification of postsynaptic structure / labyrinthine layer development / 2-oxoglutarate-dependent dioxygenase activity ...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 / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / regulation of modification of postsynaptic structure / labyrinthine layer development / 2-oxoglutarate-dependent dioxygenase activity / heart trabecula formation / cardiac muscle tissue morphogenesis / L-ascorbic acid binding / response to nitric oxide / ventricular septum morphogenesis / enzyme inhibitor activity / regulation of angiogenesis / regulation of neuron apoptotic process / ferrous iron binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cellular response to hypoxia / intracellular iron ion homeostasis / response to hypoxia / postsynaptic density / intracellular membrane-bounded organelle / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleus / cytoplasm / cytosol
Similarity search - Function
: / 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 signature. / Zinc finger, MYND-type / Zinc finger MYND-type profile. / q2cbj1_9rhob like domain ...: / 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 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. / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
BICARBONATE ION / : / Chem-UN9 / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8995 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: 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.
#2: 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.
History
DepositionJun 16, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 31, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Nov 29, 2017Group: Database references / Category: pdbx_database_related
Revision 1.3Jan 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.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 1.4Nov 13, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,7736
Polymers28,1841
Non-polymers5895
Water2,378132
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1160 Å2
ΔGint-37 kcal/mol
Surface area11780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.766, 109.766, 39.545
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

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Protein , 1 types, 1 molecules A

#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: 28184.080 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN (181-426) / Mutation: K293K, G294E
Source method: isolated from a genetically manipulated source
Details: FRAGMENT: CATALYTIC DOMAIN (181-426) / 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

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Non-polymers , 5 types, 137 molecules

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


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#3: 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
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 61.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CHO3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / 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: 2.72 Å3/Da / Density % sol: 54.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M MES pH 6.5, 1.8 M ammonium sulphate, 2% v/v dioxane, 0.002 M MnCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 11, 2015 / 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: 1.8995→47.53 Å / Num. obs: 21775 / % possible obs: 100 % / Redundancy: 14.7 % / Biso Wilson estimate: 35 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.083 / Net I/σ(I): 30.8
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 14.9 % / Rmerge(I) obs: 1 / Mean I/σ(I) obs: 2.5 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000706Edata reduction
HKL-2000706Edata scaling
PHASERphasing
PHENIX(1.10_2155: ???)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4BQX

4bqx


Resolution: 1.8995→47.53 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1847 1026 4.72 %Random
Rwork0.1595 ---
obs0.1607 21759 100 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 60.2 Å2 / ksol: 0.42 e/Å3
Displacement parametersBiso mean: 51 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å20 Å20 Å2
2---0.11 Å20 Å2
3---0.22 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.26 Å
Refinement stepCycle: LAST / Resolution: 1.8995→47.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1734 0 34 132 1900
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081880
X-RAY DIFFRACTIONf_angle_d0.9472553
X-RAY DIFFRACTIONf_dihedral_angle_d16.4631127
X-RAY DIFFRACTIONf_chiral_restr0.056266
X-RAY DIFFRACTIONf_plane_restr0.006336
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8995-1.99970.27441410.26292928X-RAY DIFFRACTION100
1.9997-2.1250.28271220.20812953X-RAY DIFFRACTION100
2.125-2.2890.18891430.18382962X-RAY DIFFRACTION100
2.289-2.51940.21821420.17282929X-RAY DIFFRACTION100
2.5194-2.88390.20651840.16722927X-RAY DIFFRACTION100
2.8839-3.63320.19211330.15462995X-RAY DIFFRACTION100
3.6332-47.54490.15051610.13713039X-RAY DIFFRACTION100
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)
10.35930.42770.19090.74810.23940.11020.3556-0.1322-0.63180.2931-0.03460.3377-0.0828-0.00580.02860.45040.02890.04560.32580.15790.545937.43392.33693.2714
20.1227-0.0329-0.03480.2522-0.3520.51580.0866-0.1855-0.68670.28090.0214-0.00781.11970.16260.02770.3947-0.13740.04120.33660.09340.382931.51479.36852.1975
31.47410.92360.43650.62040.30070.2001-0.1009-0.62840.51350.2908-0.45381.10510.2151-0.6063-0.26670.4517-0.05730.21090.5530.02050.37924.70223.939613.8472
41.68410.2919-0.11631.79031.69441.5978-0.1973-0.1240.6733-0.12840.01430.0619-0.75330.14220.00040.4443-0.0084-0.0140.40840.01370.43333.860835.94064.001
50.66210.1520.77330.12370.08750.8322-0.1516-0.4724-0.42170.9232-0.0663-0.03990.5063-0.3955-0.00050.49840.01390.03330.44660.1540.353538.093813.438113.8738
60.31540.10540.16050.11860.03190.0951-0.0422-0.3276-0.7218-0.24890.4093-0.2920.41170.60090.00010.40050.0156-0.02370.4790.08150.592550.14098.00435.0858
70.1622-0.14990.09730.69740.38960.24040.0819-0.32320.40180.1545-0.1452-0.0557-0.0219-0.17420.00070.31730.013-0.01690.34850.05280.349936.080726.31174.9097
80.63570.1693-0.2960.5859-0.30790.6181-0.0010.05940.747-0.3369-0.1141-0.5717-0.12090.01990.00010.32850.00510.01270.36610.10550.366141.572725.1939-6.7949
90.6521-0.22480.83132.0066-0.04771.26780.1511-0.1847-0.22960.1004-0.07920.23710.1496-0.2161-00.2574-0.02260.03230.33530.10.332531.238718.70862.4847
100.43050.56940.26980.83430.57260.3928-0.13030.9999-1.0206-0.6222-0.19490.44210.1887-0.4493-0.0020.32580.0133-0.00450.4373-0.03150.3630.567218.1861-10.783
110.4942-0.11320.2940.4360.13620.6987-0.28250.3151-0.49810.1-0.04540.48120.6636-0.5322-0.03160.3825-0.07020.00040.46810.00030.375628.004915.0776-5.8276
120.5193-0.34540.32110.86950.32230.5971-0.0299-0.19920.1391-0.1340.0308-0.12230.29060.22440.00010.3137-0.00580.03110.30320.06840.316840.230814.2604-3.1607
130.36840.41110.10690.58920.31140.17820.17120.2815-0.3578-0.6368-0.2010.342-0.16340.02380.00130.34010.0609-0.0460.36320.0640.334630.842624.084-8.2877
140.39170.50650.50590.89690.30090.6605-0.0806-0.4445-0.47020.09530.1470.11050.0179-0.11250.00010.24530.0038-0.00120.30390.06810.294637.645321.28224.2088
150.0164-0.00410.03370.0305-0.17140.9972-0.12950.11720.1738-0.11740.34050.1850.28790.18160.00080.23770.0415-0.02690.38020.03130.500758.513821.13852.4591
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 188:204)
2X-RAY DIFFRACTION2(chain A and resid 205:215)
3X-RAY DIFFRACTION3(chain A and resid 216:232)
4X-RAY DIFFRACTION4(chain A and resid 233:266)
5X-RAY DIFFRACTION5(chain A and resid 267:283)
6X-RAY DIFFRACTION6(chain A and resid 284:293)
7X-RAY DIFFRACTION7(chain A and resid 294:306)
8X-RAY DIFFRACTION8(chain A and resid 307:320)
9X-RAY DIFFRACTION9(chain A and resid 321:335)
10X-RAY DIFFRACTION10(chain A and resid 336:350)
11X-RAY DIFFRACTION11(chain A and resid 351:361)
12X-RAY DIFFRACTION12(chain A and resid 362:371)
13X-RAY DIFFRACTION13(chain A and resid 372:381)
14X-RAY DIFFRACTION14(chain A and resid 382:392)
15X-RAY DIFFRACTION15(chain A and resid 393:404)

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