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- PDB-5ox5: HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with CCT6, a GS... -

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Basic information

Entry
Database: PDB / ID: 5ox5
TitleHIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with CCT6, a GSK1278863-related compound
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
Chem-B2E / BICARBONATE ION / : / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.251 Å
AuthorsChowdhury, R. / Thinnes, C.C. / Schofield, C.J.
Citation
Journal: Chem Sci / Year: 2017
Title: Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.
Authors: Yeh, T.L. / Leissing, T.M. / Abboud, M.I. / Thinnes, C.C. / Atasoylu, O. / Holt-Martyn, J.P. / Zhang, D. / Tumber, A. / Lippl, K. / Lohans, C.T. / Leung, I.K.H. / Morcrette, H. / Clifton, I. ...Authors: Yeh, T.L. / Leissing, T.M. / Abboud, M.I. / Thinnes, C.C. / Atasoylu, O. / Holt-Martyn, J.P. / Zhang, D. / Tumber, A. / Lippl, K. / Lohans, C.T. / Leung, I.K.H. / Morcrette, H. / Clifton, I.J. / Claridge, T.D.W. / Kawamura, A. / Flashman, E. / Lu, X. / Ratcliffe, P.J. / Chowdhury, R. / Pugh, C.W. / 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: PLoS ONE / Year: 2015
Title: Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.
Authors: Chan, M.C. / Atasoylu, O. / Hodson, E. / Tumber, A. / Leung, I.K. / Chowdhury, R. / Gomez-Perez, V. / Demetriades, M. / Rydzik, A.M. / Holt-Martyn, J. / Tian, Y.M. / Bishop, T. / Claridge, T. ...Authors: Chan, M.C. / Atasoylu, O. / Hodson, E. / Tumber, A. / Leung, I.K. / Chowdhury, R. / Gomez-Perez, V. / Demetriades, M. / Rydzik, A.M. / Holt-Martyn, J. / Tian, Y.M. / Bishop, T. / Claridge, T.D. / Kawamura, A. / Pugh, C.W. / Ratcliffe, P.J. / Schofield, C.J.
History
DepositionSep 6, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 18, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 17, 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

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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)28,4704
Polymers28,0971
Non-polymers3733
Water1,53185
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration, MONOMER IN SOLUTION
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area260 Å2
ΔGint-6 kcal/mol
Surface area11070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)110.147, 110.147, 39.368
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: 28096.941 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP residues 181-426
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-B2E / (6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)glycine


Mass: 257.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H11N3O6
#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.: 85 / 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: 2.77 Å3/Da / Density % sol: 55.68 % / Description: Hexagonal
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 1.5 M sodium citrate tribasic dehydrate pH 6.5, Sitting drop (300 nl), protein-to-well ratio, 1:1.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 5, 2015 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.25→47.69 Å / Num. obs: 13170 / % possible obs: 100 % / Redundancy: 5.7 % / Biso Wilson estimate: 40 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.138 / Rpim(I) all: 0.064 / Net I/σ(I): 12.9
Reflection shellResolution: 2.25→2.33 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.953 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1314 / CC1/2: 0.598 / Rpim(I) all: 0.449 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-2000706Edata reduction
HKL-2000706Edata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4BQX

4bqx


Resolution: 2.251→47.69 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2048 645 4.9 %RANDOM
Rwork0.1747 ---
obs0.1761 13160 99.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 63 Å2 / ksol: 0.43 e/Å3
Displacement parametersBiso mean: 58 Å2
Baniso -1Baniso -2Baniso -3
1-4.95 Å20 Å20 Å2
2--4.95 Å20 Å2
3----9.89 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.25 Å
Luzzati d res low-5 Å
Luzzati sigma a-0.31 Å
Refinement stepCycle: LAST / Resolution: 2.251→47.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1676 0 23 85 1784
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0031735
X-RAY DIFFRACTIONf_angle_d0.5532359
X-RAY DIFFRACTIONf_dihedral_angle_d15.4711003
X-RAY DIFFRACTIONf_chiral_restr0.045253
X-RAY DIFFRACTIONf_plane_restr0.003310
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2515-2.42530.28121000.24722475X-RAY DIFFRACTION98
2.4253-2.66940.24751360.23292472X-RAY DIFFRACTION100
2.6694-3.05560.27411260.20122495X-RAY DIFFRACTION100
3.0556-3.84950.18431370.16162502X-RAY DIFFRACTION100
3.8495-47.70570.17361460.14862571X-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)
10.14060.06010.06560.1625-0.01280.04910.0430.0336-0.55860.0436-0.0690.17360.5714-0.16670.00470.5165-0.00640.04460.3450.13480.502490.3643-90.185.0384
20.34250.06940.25980.03020.05550.26850.0098-0.80680.27070.5999-0.20210.3883-0.1614-0.5941-0.02190.4320.10570.10410.64960.08630.407380.0893-71.198915.7005
31.51510.0454-1.5850.09480.07951.6798-0.43640.11380.2917-0.1386-0.28790.1436-0.5681-0.1897-0.31660.6387-0.0509-0.1380.35850.02450.581587.425-53.89810.8655
40.13980.0915-0.11410.09950.02440.08080.0395-0.13810.37670.15220.0910.4039-0.1695-0.38770.00010.43280.02870.02330.53360.02210.410691.0163-65.439812.8605
51.36160.14470.90170.88330.38190.60560.0520.00680.01580.1601-0.0379-0.0866-0.0394-0.0031-00.30440.0465-0.00410.30220.08360.299295.2323-76.57296.214
60.30750.4140.32410.9855-0.04080.50220.08170.6543-0.5111-0.30580.00120.14850.1525-0.2826-0.00080.268-0.0099-0.03990.47480.02460.352883.3842-76.8137-5.6339
70.6062-0.02640.97921.09520.21760.1945-0.00230.0735-0.046-0.00260.0225-0.02440.119-0.067-0.0010.28110.0267-0.00420.34370.06780.340594.3367-75.89291.2672
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 231 )
3X-RAY DIFFRACTION3chain 'A' and (resid 232 through 251 )
4X-RAY DIFFRACTION4chain 'A' and (resid 252 through 266 )
5X-RAY DIFFRACTION5chain 'A' and (resid 267 through 329 )
6X-RAY DIFFRACTION6chain 'A' and (resid 330 through 353 )
7X-RAY DIFFRACTION7chain 'A' and (resid 354 through 403 )

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