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- PDB-5lbc: HIF prolyl hydroxylase 2 (PHD2/EGLN1) I280V/R281L/I292V variant i... -

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Basic information

Entry
Database: PDB / ID: 5lbc
TitleHIF prolyl hydroxylase 2 (PHD2/EGLN1) I280V/R281L/I292V 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: 1.816 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

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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)28,8339
Polymers28,0251
Non-polymers8088
Water2,486138
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1690 Å2
ΔGint-43 kcal/mol
Surface area11490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)111.006, 111.006, 40.283
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: 28024.854 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN (181-426) / Mutation: I280V, R281L, I292V
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 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9GZT9, hypoxia-inducible factor-proline dioxygenase

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Non-polymers , 7 types, 146 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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: 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
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-BCT / BICARBONATE ION


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


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O

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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: 2.88 Å3/Da / Density % sol: 57.29 %
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, 5% v/v dioxane, 0.002 M MnCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9173 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 17, 2011 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 1.81→48.067 Å / Num. obs: 25773 / % possible obs: 99.5 % / Redundancy: 5.3 % / Biso Wilson estimate: 25.1 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.092 / Net I/σ(I): 17.1
Reflection shellResolution: 1.81→1.87 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.729 / Mean I/σ(I) obs: 2 / % possible all: 98.5

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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: 4BQX

4bqx


Resolution: 1.816→48.067 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 16.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1809 1360 5.28 %
Rwork0.1577 --
obs0.1589 25762 99.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 58.9 Å2 / ksol: 0.42 e/Å3
Displacement parametersBiso mean: 39 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å20 Å20 Å2
2--0.06 Å20 Å2
3----0.12 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.21 Å
Refinement stepCycle: LAST / Resolution: 1.816→48.067 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1702 0 47 138 1887
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061868
X-RAY DIFFRACTIONf_angle_d0.952543
X-RAY DIFFRACTIONf_dihedral_angle_d15.2041092
X-RAY DIFFRACTIONf_chiral_restr0.055271
X-RAY DIFFRACTIONf_plane_restr0.006334
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8156-1.88050.23811070.25882392X-RAY DIFFRACTION97
1.8805-1.95580.24051450.22182385X-RAY DIFFRACTION98
1.9558-2.04480.18721470.18122417X-RAY DIFFRACTION100
2.0448-2.15260.17781560.16672382X-RAY DIFFRACTION100
2.1526-2.28750.16331330.15582459X-RAY DIFFRACTION100
2.2875-2.46410.15051220.1492455X-RAY DIFFRACTION100
2.4641-2.7120.19321220.14982463X-RAY DIFFRACTION100
2.712-3.10440.18361460.1452460X-RAY DIFFRACTION100
3.1044-3.9110.15771350.14352462X-RAY DIFFRACTION100
3.911-48.08380.19041470.1542527X-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)
10.3030.15010.10180.62750.02750.1397-0.0660.0711-0.47510.08280.0349-0.42540.08480.22190.04190.23310.05110.06510.307-0.05440.4405145.225664.38590.5973
20.68460.62260.27190.79940.56071.89210.24120.1632-0.2054-0.12930.0509-0.84350.45710.45220.43740.17340.00860.1410.2939-0.03340.3882142.128273.23341.333
30.28960.16030.21880.12350.10010.3273-0.23930.40810.6795-0.69080.1673-0.2428-0.29560.1518-0.10320.3955-0.07920.13460.29060.0660.3023132.92486.6163-10.2177
41.3990.74140.87461.2619-0.28560.8061-0.00980.00490.3115-0.1914-0.21680.5089-0.2941-0.4461-0.07580.2620.0339-0.01320.259-0.02290.2377118.021984.0729-0.8568
51.4560.64160.61461.08040.92650.6939-0.13570.7266-0.584-0.86570.3259-0.4202-0.30640.2550.20080.29860.02040.16150.294-0.12080.3162135.747569.6613-9.5006
60.020.04180.04150.06320.0682-0.00480.6695-0.3334-0.5826-0.1217-0.1438-0.65330.42660.1842-00.2721-0.0046-0.02270.2708-0.03670.4473134.394756.6173-0.7238
70.2263-0.05110.16420.0531-0.06240.0764-0.05230.11850.1558-0.14470.08450.1167-0.19850.14570.00080.21260.00190.00220.1725-0.03770.1955125.266278.8889-1.2107
80.4567-0.0689-0.14780.0852-0.01610.2049-0.0687-0.1953-0.09470.2852-0.14450.50250.0229-0.1844-0.03350.2361-0.02310.05250.201-0.02290.2168123.221672.377910.0676
90.9049-0.325-0.39660.4157-0.0830.6298-0.0588-0.2074-0.0243-0.36120.0114-0.50120.07970.29050.04860.1628-0.03870.06390.1998-0.04850.2434134.154178.14161.1506
100.8833-0.1314-0.01710.21520.06040.11360.1344-0.55650.06790.6865-0.1643-0.58170.24120.09250.11890.3418-0.0388-0.07980.26620.00460.2205134.721478.980113.8624
110.1302-0.1026-0.01190.27430.2160.11-0.0667-0.2973-0.09350.1982-0.0837-0.83990.15740.62690.04680.2837-0.0434-0.03850.31430.01460.2841138.731779.36868.9229
120.0873-0.03740.04640.16580.10690.0452-0.09360.0881-0.2653-0.10420.1117-0.30470.1520.00590.00010.19480.00890.01730.19560.00190.2216133.368668.11476.5409
130.66650.0185-0.02630.1518-0.04230.101-0.0903-0.24630.12140.43650.0071-0.1799-0.24930.0061-0.03760.2873-0.0032-0.00530.1922-0.03320.1506129.497781.132811.8251
140.40330.03060.06260.43570.2158-0.0292-0.04080.033-0.1326-0.25340.0115-0.2561-0.02620.1197-0.01220.1826-0.00770.02560.1519-0.02470.1701128.753973.8021-0.9629
150.0335-0.04980.01820.0339-0.01310.03930.0703-0.05670.34320.48380.110.1098-0.0366-0.0847-0.00010.2440.00610.02020.1969-0.02120.3221119.641455.24840.7607
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 393:402)

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