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- PDB-5lbb: HIF prolyl hydroxylase 2 (PHD2/EGLN1) R396T variant in complex wi... -

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Basic information

Entry
Database: PDB / ID: 5lbb
TitleHIF prolyl hydroxylase 2 (PHD2/EGLN1) R396T 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


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 / intracellular oxygen homeostasis / labyrinthine layer development / cardiac muscle tissue morphogenesis ...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 / intracellular oxygen homeostasis / labyrinthine layer development / cardiac muscle tissue morphogenesis / 2-oxoglutarate-dependent dioxygenase activity / heart trabecula formation / regulation of modification of postsynaptic structure / L-ascorbic acid binding / response to nitric oxide / ventricular septum morphogenesis / regulation of angiogenesis / ferrous iron binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / negative regulation of DNA-binding transcription factor activity / cellular response to hypoxia / intracellular iron ion homeostasis / postsynaptic density / response to hypoxia / intracellular membrane-bounded organelle / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / 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. / q2cbj1_9rhob like domain / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Oxoglutarate/iron-dependent dioxygenase ...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. / q2cbj1_9rhob like domain / 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. / 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: 1.7 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

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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)28,4374
Polymers28,0411
Non-polymers3973
Water2,198122
1
A: Egl nine homolog 1
hetero molecules

A: Egl nine homolog 1
hetero molecules

A: Egl nine homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,31212
Polymers84,1233
Non-polymers1,1909
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_445-y-1,x-y-1,z1
crystal symmetry operation3_545-x+y,-x-1,z1
Buried area9250 Å2
ΔGint-62 kcal/mol
Surface area28000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.199, 110.199, 39.717
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#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: 28040.852 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 181-426 / Mutation: R396T
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
#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-BCT / BICARBONATE ION


Mass: 61.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CHO3 / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.74 Å3/Da / Density % sol: 55.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M MES pH 6.5, 2.1 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: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 24, 2013 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.7→36.67 Å / Num. obs: 29903 / % possible obs: 97.8 % / Redundancy: 3.3 % / Biso Wilson estimate: 31.4 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.038 / Net I/σ(I): 14.5
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.701 / Mean I/σ(I) obs: 2.2 / % possible all: 97.6

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Processing

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

4bqx


Resolution: 1.7→36.071 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1781 1500 5.02 %
Rwork0.1521 --
obs0.1534 29896 97.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 59.4 Å2 / ksol: 0.43 e/Å3
Displacement parametersBiso mean: 46 Å2
Baniso -1Baniso -2Baniso -3
1--1.84 Å20 Å20 Å2
2---1.84 Å20 Å2
3---3.68 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.32 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.24 Å
Refinement stepCycle: LAST / Resolution: 1.7→36.071 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1747 0 24 122 1893
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0171857
X-RAY DIFFRACTIONf_angle_d1.4512522
X-RAY DIFFRACTIONf_dihedral_angle_d16.4651100
X-RAY DIFFRACTIONf_chiral_restr0.079268
X-RAY DIFFRACTIONf_plane_restr0.011334
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.75490.25651300.23692552X-RAY DIFFRACTION97
1.7549-1.81760.23791250.21092577X-RAY DIFFRACTION98
1.8176-1.89040.231530.19262583X-RAY DIFFRACTION98
1.8904-1.97640.2031460.18272572X-RAY DIFFRACTION99
1.9764-2.08060.23041230.16342620X-RAY DIFFRACTION99
2.0806-2.2110.19111320.15312588X-RAY DIFFRACTION98
2.211-2.38160.16491350.14492588X-RAY DIFFRACTION98
2.3816-2.62130.19181440.15492594X-RAY DIFFRACTION98
2.6213-3.00040.19421420.15822553X-RAY DIFFRACTION96
3.0004-3.77950.17481400.1432524X-RAY DIFFRACTION95
3.7795-36.07920.14751300.14062645X-RAY DIFFRACTION96
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)
10.22650.28990.16222.53250.62640.23810.17960.33180.34270.26570.3869-0.2988-0.2866-0.80350.20950.2681-0.01190.10460.50010.12410.400616.3028-33.653-1.6134
20.8587-0.4617-0.36920.79190.45890.5437-0.26290.14130.488-0.13050.2429-0.4648-0.20760.55140.15360.3796-0.13080.03740.28520.09180.33687.7357-32.42810.1593
30.4037-0.4292-0.11050.97880.56770.7512-0.2610.05810.3249-0.6973-0.16860.4423-0.23130.0423-0.220.45440.0497-0.0370.4230.15610.3835-9.2286-34.3085-11.3347
41.38270.23571.15741.04990.35110.85970.00490.2886-0.14860.0508-0.18120.45670.0857-0.6425-00.3315-0.02030.04820.389-0.01630.3814-14.3438-47.7321-1.8283
50.065-0.0757-0.00031.01270.52780.30460.00980.52620.13-0.2758-0.0412-0.5615-0.47090.08570.02290.3953-0.02190.07370.51450.10910.34587.2564-39.8682-11.405
60.1168-0.08-0.11140.19850.13480.09170.17970.17770.09750.58430.1264-0.73350.15420.44370.00050.45270.02720.02360.4481-0.03190.495317.9638-47.1395-2.1559
70.36870.27980.49720.35430.46850.5482-0.08310.10.0223-0.0447-0.01040.1247-0.006-0.0874-0.00020.2640.01590.05410.293-0.00040.3132-5.889-43.8259-2.3495
80.60110.248-0.18860.61480.0730.7489-0.2214-0.2458-0.77360.1937-0.03240.29040.27620.0416-0.0050.28850.03080.08970.28190.07840.2998-1.1379-48.58589.4605
90.90130.87370.20450.70510.01130.9845-0.17470.02090.30220.15010.0863-0.2169-0.20840.0864-0.00030.290.01450.05750.22240.05380.2674-0.4341-36.8447-0.0645
100.22150.3420.05020.63990.40540.4262-0.1968-0.49910.32470.56370.1706-0.3065-0.3052-0.00730.00450.35040.05780.00750.3291-0.02640.2843-0.6174-36.196712.7345
110.50240.025-0.21440.45480.29150.2366-0.1308-0.12120.5090.3752-0.3359-0.1119-0.89510.49940.00070.3863-0.0348-0.00130.32830.04960.32560.8355-32.14228.0304
120.20.00470.0970.13430.03-0.01860.05780.0348-0.0484-0.1018-0.0261-0.2217-0.02990.33590.00010.27830.00640.03130.27880.05250.2947.7861-43.00955.9328
130.69990.4395-0.11650.82620.26930.233-0.0257-0.79850.39050.282-0.0551-0.0438-0.0355-0.12730.02910.29090.05310.08280.3216-0.03540.2913-5.5386-39.032610.4679
140.48180.68370.21620.88550.52330.29980.12510.14560.125-0.1807-0.0993-0.1665-0.1194-0.0079-0.00010.24610.01650.06130.23320.03510.26350.1558-43.387-2.1691
150.1964-0.0843-0.01880.2027-0.070.26-0.03930.00930.13440.01520.18090.55180.5274-0.0277-00.3470.02650.01270.3359-0.02940.454710.3678-61.9708-0.7727
161.64441.0840.7630.72060.49890.3576-0.1028-0.72390.5677-0.2761-0.14950.65790.3516-0.85750.03340.7164-0.0243-0.20970.58350.20910.5135.3574-74.3541-9.2705
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 393:405)
16X-RAY DIFFRACTION16(chain A and resid 411:417)

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