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- PDB-5lat: HIF prolyl hydroxylase 2 (PHD2/EGLN1) P317R variant in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5lat
TitleHIF prolyl hydroxylase 2 (PHD2/EGLN1) P317R variant in complex with Mn(II) and N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine (IOX3/UN9)
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 / regulation of angiogenesis / enzyme inhibitor activity / 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: 1.9 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 15, 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 16, 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)28,6465
Polymers28,1571
Non-polymers4894
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint-14 kcal/mol
Surface area11450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.182, 111.182, 40.028
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: 28157.020 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP residues 181-426 / Mutation: P317R
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

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Non-polymers , 5 types, 190 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#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.: 186 / 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: 2.87 Å3/Da / Density % sol: 57.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 0.1 M tri-sodium citrate pH 5.6, 20% PEG 4000, 20% 2-propanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 29, 2007 / 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: 1.9→27.8 Å / Num. obs: 22463 / % possible obs: 99.6 % / Redundancy: 2.8 % / Biso Wilson estimate: 21.36 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.088 / Net I/σ(I): 9.1
Reflection shellResolution: 1.9→2 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.354 / Mean I/σ(I) obs: 2.9 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4BQX

4bqx


Resolution: 1.9→27.796 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 16.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1659 1149 5.12 %
Rwork0.1504 --
obs0.1512 22455 99.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 68.8 Å2 / ksol: 0.42 e/Å3
Displacement parametersBiso mean: 33 Å2
Baniso -1Baniso -2Baniso -3
1--2.87 Å20 Å20 Å2
2---2.87 Å20 Å2
3---5.75 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.24 Å
Refinement stepCycle: LAST / Resolution: 1.9→27.796 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1718 0 30 186 1934
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061838
X-RAY DIFFRACTIONf_angle_d0.8522491
X-RAY DIFFRACTIONf_dihedral_angle_d14.4771096
X-RAY DIFFRACTIONf_chiral_restr0.052261
X-RAY DIFFRACTIONf_plane_restr0.005328
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9001-1.98660.24361470.2032648X-RAY DIFFRACTION100
1.9866-2.09130.21221520.17182613X-RAY DIFFRACTION100
2.0913-2.22230.18591440.15012670X-RAY DIFFRACTION100
2.2223-2.39380.1641460.14742622X-RAY DIFFRACTION100
2.3938-2.63450.18551530.14162685X-RAY DIFFRACTION100
2.6345-3.01530.17421390.13822660X-RAY DIFFRACTION100
3.0153-3.79740.14051330.13722659X-RAY DIFFRACTION99
3.7974-27.79850.13991350.15512749X-RAY DIFFRACTION99
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)
10.177-0.1492-0.09650.39150.24530.15130.02320.0135-0.1767-0.0376-0.04150.4236-0.2139-0.04630.01010.194-0.04170.07090.22170.05490.365721.0757-31.79692.0936
20.6159-0.64610.53050.7273-0.37431.47860.23360.07970.017-0.01420.10460.30070.023-0.15410.30060.1044-0.02670.0980.19040.02690.300424.4638-23.37440.5152
30.1736-0.03270.1820.1572-0.1450.4189-0.0802-0.24420.22620.22510.05820.13-0.3482-0.17910.00170.34960.03720.15120.1888-0.08050.24333.9237-9.590812.1127
41.1962-0.43860.25130.68870.13010.498-0.01360.09330.35330.3328-0.0962-0.296-0.04050.1384-0.1480.1879-0.0109-0.00410.14060.00940.170948.6256-11.71662.5278
50.5531-0.32750.19050.232-0.0380.20770.0542-0.2716-0.11870.39040.0560.2744-0.1615-0.10320.33530.2734-0.06770.27510.16380.11550.121431.0215-26.641511.949
60.0162-0.00490.03450.0013-0.00970.07710.10620.1008-0.17210.0551-0.03260.2710.17160.13210.00040.18690.00830.02040.16810.03780.32831.801-39.77423.2169
70.29760.0242-0.00190.0030.00150.00170.0795-0.06680.1970.0787-0.0887-0.0279-0.04390.004-0.00050.1883-0.01290.01760.09850.03560.109541.2258-17.44953.1982
80.15150.07280.00860.10750.01050.0713-0.02110.1219-0.0776-0.2668-0.096-0.24370.06580.0688-0.02870.17640.01350.06760.13140.01540.137643.5606-24.6864-8.5815
90.2941-0.00190.01530.01280.05530.39430.05530.07120.16460.0341-0.00090.23830.012-0.17570.10570.10520.03230.08030.10920.04660.213432.2107-17.75430.9072
100.28650.223-0.10010.1808-0.0870.04240.08740.38960.1369-0.14440.00210.32960.1636-0.10320.02650.23670.0361-0.05920.20360.02110.187431.9449-18.1386-12.0988
110.0580.0823-0.0870.1392-0.10480.12640.0990.29050.1996-0.1698-0.0540.41450.0128-0.25160.01330.21530.0605-0.01090.28410.02260.238127.6227-17.1936-7.3494
120.0120.0080.00490.031-0.01170.00960.08490.0942-0.08530.0322-0.01640.06970.1828-0.14830.00050.17380.0010.01950.1499-0.00080.167532.6984-28.0094-4.2146
130.125-0.01060.01240.0070.00820.0178-0.00240.22870.1233-0.22280.03790.1044-0.1527-0.10530.00050.18120.00130.0060.14320.04060.125736.8976-15.1536-9.7289
140.0666-0.08750.07550.3667-0.05730.1334-0.0571-0.035-0.08170.14520.1230.1634-0.0602-0.11520.00160.12020.00630.05050.07260.01760.133537.7264-22.55033.013
150.00940.003-0.00590.0075-0.00950.01290.0565-0.01670.083-0.0479-0.0018-0.02790.01360.1557-0.00010.182-0.01590.00360.13740.00860.19848.665-40.42870.345
160.0351-0.02270.00930.0219-0.00720.00270.0035-0.0450.01740.0359-0.04620.03180.00260.0080.00010.690.0628-0.13290.8677-0.07770.600262.6601-44.036111.0366
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)
16X-RAY DIFFRACTION16(chain A and resid 408:411)

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