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- PDB-5lb6: HIF prolyl hydroxylase 2 (PHD2/EGLN1) R371H variant in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5lb6
TitleHIF prolyl hydroxylase 2 (PHD2/EGLN1) R371H 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
: / Chem-UN9 / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 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 1.2Jan 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.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 1.3Oct 23, 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)28,6025
Polymers28,0781
Non-polymers5244
Water3,117173
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-23 kcal/mol
Surface area11510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.159, 111.159, 40.380
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: 28077.895 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 181-426 / Mutation: R371H
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

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Non-polymers , 5 types, 177 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.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 173 / 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: 2.9 Å3/Da / Density % sol: 57.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M MES-Na pH 6.5, 30% polyethylene glycol monomethyl ether 5000, 0.2 M ammonium sulphate

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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: 1.7→37.24 Å / Num. obs: 31671 / % possible obs: 100 % / Redundancy: 10.5 % / Biso Wilson estimate: 20.1 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.086 / Net I/σ(I): 16.7
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 10.7 % / Rmerge(I) obs: 0.498 / Mean I/σ(I) obs: 4.4 / % possible all: 100

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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: 1.7→36.385 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 14.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1682 1462 4.62 %
Rwork0.1451 --
obs0.1461 31646 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 56.6 Å2 / ksol: 0.43 e/Å3
Displacement parametersBiso mean: 34 Å2
Baniso -1Baniso -2Baniso -3
1--0.91 Å20 Å20 Å2
2---0.91 Å20 Å2
3---1.82 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.19 Å
Refinement stepCycle: LAST / Resolution: 1.7→36.385 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1711 0 31 173 1915
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0121857
X-RAY DIFFRACTIONf_angle_d1.2152525
X-RAY DIFFRACTIONf_dihedral_angle_d14.8911095
X-RAY DIFFRACTIONf_chiral_restr0.072265
X-RAY DIFFRACTIONf_plane_restr0.009332
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.76080.21221510.17952979X-RAY DIFFRACTION100
1.7608-1.83130.18391420.16963014X-RAY DIFFRACTION100
1.8313-1.91460.15491560.14562977X-RAY DIFFRACTION100
1.9146-2.01560.17761470.13892989X-RAY DIFFRACTION100
2.0156-2.14180.17071410.13543009X-RAY DIFFRACTION100
2.1418-2.30720.13281340.13483008X-RAY DIFFRACTION100
2.3072-2.53930.17071810.13523005X-RAY DIFFRACTION100
2.5393-2.90660.15991320.13913030X-RAY DIFFRACTION100
2.9066-3.66150.18141300.14083063X-RAY DIFFRACTION100
3.6615-36.39360.1671480.15363110X-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)
11.5498-0.50351.13472.5324-1.59744.24890.0593-0.1932-0.36490.02630.0533-0.55120.2457-0.0308-0.1250.20420.0408-0.10440.27820.03820.539772.7317130.56182.9369
20.46281.0415-0.32792.4473-1.28613.80280.1401-0.1485-0.51720.05070.186-0.31120.36330.1232-0.19590.22710.0483-0.06690.19660.06620.415363.5043128.96521.6105
37.0183-4.39610.00764.9028-0.03791.32290.0691-0.3403-0.50350.5155-0.04170.39390.3507-0.139-0.07610.3644-0.107-0.02870.27540.13370.239747.3434130.095313.1713
42.5584-0.16270.79562.9768-0.18743.47480.1345-0.160.12760.0463-0.15970.5837-0.1383-0.2650.01530.1888-0.02220.00090.1991-0.01020.226941.2354144.02433.115
52.10650.1731-0.63831.42390.14780.61480.0893-0.5792-0.22370.4828-0.1079-0.42940.24050.02640.19760.3156-0.0545-0.21090.34740.16970.245963.0129136.307713.125
62.5686-1.6128-2.11593.14081.94421.93840.1003-0.2694-0.24930.12690.0039-0.5910.14570.2395-0.0910.2095-0.0036-0.07190.22770.00620.421774.0998144.09233.709
74.66271.37881.2891.92380.41981.19630.0707-0.1095-0.03820.0738-0.04320.15250.03310.0055-0.05810.1505-0.0291-0.02670.16910.00430.131950.1668140.68794.1068
83.57311.79780.97042.26190.7291.4979-0.20.32630.3939-0.28030.03530.0584-0.17070.03830.12920.1973-0.0239-0.04350.1750.05030.162454.7316145.7186-7.1745
92.1661.41010.01862.74920.24181.31080.0837-0.0026-0.338-0.112-0.02080.0210.28440.0712-0.01650.16410.0031-0.07510.11620.03620.222455.8167133.92871.7945
102.8617-1.4555-0.06380.78960.3351.8645-0.07840.5137-0.5096-0.73470.1028-0.10270.1440.2789-0.06470.3382-0.030.00610.289-0.0950.224854.9214132.4775-11.1504
112.16110.3473-0.36142.8469-1.51647.74630.00880.201-0.577-0.42470.0082-0.38340.45360.2640.02510.26790.0163-0.00430.1709-0.02780.278156.7809128.8347-6.566
121.2982-1.18030.89481.4368-0.6040.83710.09810.1555-0.2047-0.0921-0.0693-0.44920.09880.2924-0.0620.16550.00120.0020.1908-0.00330.210563.4636139.0171-3.5661
134.80132.3966-0.53572.1652-0.16671.0269-0.10940.4718-0.2693-0.4460.05540.04210.1457-0.11610.03470.22-0.0284-0.04220.2291-0.02860.155450.3645135.859-8.8841
141.35420.74310.19121.2880.11010.61530.1831-0.1827-0.09910.141-0.1706-0.11640.0778-0.0132-0.02590.1374-0.0266-0.04290.14650.0220.147256.3115140.23663.8972
154.1112-1.0823-0.84515.17491.01473.65940.06330.12380.1175-0.06080.01890.6059-0.3102-0.2878-0.12080.1656-0.0078-0.01450.19320.01250.278266.6657158.38181.9016
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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