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- PDB-4uwd: HIF prolyl hydroxylase 2 (PHD2/ EGLN1) D315E VARIANT in complex w... -

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Basic information

Entry
Database: PDB / ID: 4uwd
TitleHIF prolyl hydroxylase 2 (PHD2/ EGLN1) D315E 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 / IRON / 2-OXOGLUTARATE / DIOXYGENASE / HYPOXIA-INDUCIBLE FACTOR / HIF / HIF PROLYL HYDROXYLASE DOMAIN 2 / PHD2 / EGLN / OXYGENASE / HYPOXIA / DNA-BINDING / METAL-BINDING / TRANSCRIPTION / HELIX-LOOP-HELIX-BETA / DSBH / FACIAL TRIAD / ASPARAGINYL/ ASPARTYL HYDROXYLASE / TRANSCRIPTION AND EPIGENETIC REGULATION / SIGNALING / DEVELOPMENT / CELL STRUCTURE / ANKYRIN REPEAT DOMAIN / ARD / BETA-HYDROXYLATION / TRANSCRIPTION ACTIVATOR/INHIBITOR / PHOSPHORYLATION / S-NITROSYLATION
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: 1.721 Å
AuthorsChowdhury, R. / Tarhonskaya, H. / Schofield, C.J.
Citation
Journal: Biochem.J. / Year: 2014
Title: Investigating the Contribution of the Active Site Environment to the Slow Reaction of Hypoxia-Inducible Factor Prolyl Hydroxylase Domain 2 with Oxygen.
Authors: Tarhonskaya, H. / Chowdhury, R. / Leung, I.K.H. / Loik, N.D. / Mccullagh, J.S.O. / Claridge, T.D.W. / Schofield, C.J. / Flashman, E.
#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. / 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. / 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.
History
DepositionAug 11, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 27, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2014Group: Atomic model / Other
Revision 1.2Oct 22, 2014Group: Database references
Revision 1.3Mar 6, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.4May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.5Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_alt_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.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_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.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _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 / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_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)28,4473
Polymers28,1111
Non-polymers3362
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)110.520, 110.520, 39.380
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: Protein EGL NINE HOMOLOG 1 / HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE 2 / HIF-PH2 / HIF -PROLYL HYDROXYLASE 2 / HPH-2 / ...HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE 2 / HIF-PH2 / HIF -PROLYL HYDROXYLASE 2 / HPH-2 / PROLYL HYDROXYLASE DOMAIN-CONTAINING PROTEIN 2 / PHD2 / SM-20 / HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE 2


Mass: 28110.967 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 181-426 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET28A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q9GZT9, procollagen-proline 4-dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and ...References: UniProt: Q9GZT9, procollagen-proline 4-dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.6 Å3/Da / Density % sol: 52.3 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M MES PH6.5, 1.7M AMMONIUM SULFATE, 1% DIOXANE, 0.002M MNCL2, SITTING DROP, 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 17, 2013 / 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: 1.72→47.86 Å / Num. obs: 29428 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 6.6 % / Biso Wilson estimate: 29.62 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 20.4
Reflection shellResolution: 1.72→1.77 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 3 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4BQY

4bqy


Resolution: 1.721→47.857 Å / SU ML: 0.16 / σ(F): 1.35 / Phase error: 17.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1735 1497 5.1 %
Rwork0.1495 --
obs0.1507 29416 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.721→47.857 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1684 0 20 146 1850
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0091883
X-RAY DIFFRACTIONf_angle_d1.2162572
X-RAY DIFFRACTIONf_dihedral_angle_d13.787690
X-RAY DIFFRACTIONf_chiral_restr0.048270
X-RAY DIFFRACTIONf_plane_restr0.007344
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7214-1.7770.27821280.22832524X-RAY DIFFRACTION100
1.777-1.84050.21481230.19262504X-RAY DIFFRACTION100
1.8405-1.91420.20561360.17952526X-RAY DIFFRACTION100
1.9142-2.00130.17621350.17032513X-RAY DIFFRACTION100
2.0013-2.10680.16611600.15422497X-RAY DIFFRACTION100
2.1068-2.23880.15921290.14792524X-RAY DIFFRACTION100
2.2388-2.41170.16741260.14552547X-RAY DIFFRACTION100
2.4117-2.65440.18161330.15512554X-RAY DIFFRACTION100
2.6544-3.03840.17951600.15542521X-RAY DIFFRACTION100
3.0384-3.82780.16651260.14082573X-RAY DIFFRACTION100
3.8278-47.8750.16611410.13882636X-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)
11.6593-0.4622-0.71492.61490.44230.31210.12950.31640.037-0.2562-0.18440.664-0.1168-0.5230.01540.33790.0436-0.10550.40960.03670.388122.22428.1569-0.7477
23.54570.284-0.72823.54830.68171.9407-0.0195-0.0571-0.6772-0.2870.0632-0.22320.2698-0.0104-0.03040.361-0.0313-0.02310.3137-0.00840.340842.21499.0801-4.9451
33.1932-0.017-0.42662.784-0.18944.4891-0.01740.1179-0.2928-0.3345-0.3195-0.53090.47650.4650.25630.34760.01340.01630.32940.04230.354946.297313.489-5.2201
44.2404-2.3121-1.77997.39562.06272.5570.27770.69340.1402-1.1857-0.2980.3602-0.0242-0.6535-0.01280.45560.0371-0.11520.46810.05620.277731.142526.0266-12.0176
51.66190.0596-0.75073.1952-0.10541.42540.0290.00950.21080.112-0.0613-0.1606-0.1291-0.01580.02670.2407-0.0168-0.07560.25090.03480.263138.168525.68541.3951
63.68520.1802-0.63094.12110.32173.99050.0392-0.3513-0.09650.5306-0.08920.63020.2777-0.61140.09490.3029-0.051-0.01670.34880.07150.309230.204615.47359.6131
72.3017-0.2292-0.76952.43020.40751.3922-0.0137-0.06940.01820.1505-0.01830.11110.1094-0.18340.02610.2652-0.0286-0.06730.26380.03330.233733.815920.23894.0822
82.6453-0.0056-2.45650.36380.39182.9196-0.14110.0358-0.6983-0.02350.2763-0.2497-0.10610.4057-0.16690.3607-0.02880.02770.3184-0.01050.521649.462440.3077-2.8747
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND (RESID 188 THROUGH 215 )
2X-RAY DIFFRACTION2CHAIN A AND (RESID 216 THROUGH 246 )
3X-RAY DIFFRACTION3CHAIN A AND (RESID 247 THROUGH 266 )
4X-RAY DIFFRACTION4CHAIN A AND (RESID 267 THROUGH 282 )
5X-RAY DIFFRACTION5CHAIN A AND (RESID 283 THROUGH 329 )
6X-RAY DIFFRACTION6CHAIN A AND (RESID 330 THROUGH 353 )
7X-RAY DIFFRACTION7CHAIN A AND (RESID 354 THROUGH 391 )
8X-RAY DIFFRACTION8CHAIN A AND (RESID 392 THROUGH 409 )

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