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- PDB-6qgv: HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with a Spiro[4.... -

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Basic information

Entry
Database: PDB / ID: 6qgv
TitleHIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with a Spiro[4.5]decanone inhibitor (JPHM-2-167)
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 / peptidyl-proline dioxygenase activity / negative regulation of cyclic-nucleotide phosphodiesterase activity / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / labyrinthine layer development / cardiac muscle tissue morphogenesis / heart trabecula formation ...peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / peptidyl-proline dioxygenase activity / negative regulation of cyclic-nucleotide phosphodiesterase activity / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / labyrinthine layer development / cardiac muscle tissue morphogenesis / heart trabecula formation / regulation of modification of postsynaptic structure / 2-oxoglutarate-dependent dioxygenase activity / L-ascorbic acid binding / response to nitric oxide / ventricular septum morphogenesis / regulation of angiogenesis / ferrous iron binding / negative regulation of DNA-binding transcription factor activity / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / 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 / cytosol / cytoplasm
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. ...: / 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
ISOPROPYL ALCOHOL / Chem-J2H / : / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsChowdhury, R. / Holt-Martyn, J.P. / Rahman, M.Z. / Schofield, C.J.
Citation
Journal: Medchemcomm / Year: 2019
Title: Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors.
Authors: Holt-Martyn, J.P. / Tumber, A. / Rahman, M.Z. / Lippl, K. / Figg Jr., W. / McDonough, M.A. / Chowdhury, R. / 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: Medchemcomm / Year: 2019
Title: Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors.
Authors: Holt-Martyn, J.P. / Tumber, A. / Rahman, M.Z. / Lippl, K. / Figg Jr., W. / McDonough, M.A. / Chowdhury, R. / Schofield, C.J.
History
DepositionJan 13, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 20, 2021Group: Database references / Refinement description / Category: citation / citation_author / refine / Item: _refine.solvent_model_details
Revision 1.2Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _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.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Jan 24, 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)26,9407
Polymers26,0371
Non-polymers9046
Water3,243180
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area800 Å2
ΔGint-16 kcal/mol
Surface area10230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.065, 120.065, 86.563
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-505-

SO4

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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: 26036.582 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CATALYTIC DOMAIN (aa 181-407) / 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 , 6 types, 186 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-J2H / 8-[(3-methylpyridin-2-yl)methyl]-3-(4-phenylphenyl)-1-pyrimidin-2-yl-1,3,8-triazaspiro[4.5]decane-2,4-dione


Mass: 504.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H28N6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#6: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.19 Å3/Da / Density % sol: 43.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 2.0 M Ammonium sulfate, 5% v/v 2-propanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Nov 22, 2015 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.4→60.032 Å / Num. obs: 47060 / % possible obs: 100 % / Redundancy: 19.2 % / Biso Wilson estimate: 20.7 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.014 / Rrim(I) all: 0.062 / Net I/σ(I): 19
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 18.7 % / Rmerge(I) obs: 1.646 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 6828 / CC1/2: 0.754 / Rpim(I) all: 0.389 / Rrim(I) all: 1.692 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
DIALSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4BQX

4bqx


Resolution: 1.4→60.032 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 18.02
RfactorNum. reflection% reflection
Rfree0.1722 2361 5.02 %
Rwork0.1569 --
obs0.1577 46995 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Solvent model: BULK SOLVENT MODELLING METHOD USED : FLAT MODEL
Bsol: 60.8 Å2 / ksol: 0.4 e/Å3
Refinement stepCycle: LAST / Resolution: 1.4→60.032 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1524 0 59 180 1763
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0141728
X-RAY DIFFRACTIONf_angle_d1.3972368
X-RAY DIFFRACTIONf_dihedral_angle_d20.109622
X-RAY DIFFRACTIONf_chiral_restr0.098240
X-RAY DIFFRACTIONf_plane_restr0.01314
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.42860.29141460.23992603X-RAY DIFFRACTION100
1.4286-1.45970.23931250.21652610X-RAY DIFFRACTION100
1.4597-1.49360.21851300.20282618X-RAY DIFFRACTION100
1.4936-1.5310.20351290.17882605X-RAY DIFFRACTION100
1.531-1.57240.21951430.172613X-RAY DIFFRACTION100
1.5724-1.61870.17911360.1562595X-RAY DIFFRACTION100
1.6187-1.67090.17771360.15652632X-RAY DIFFRACTION100
1.6709-1.73060.16831500.14292579X-RAY DIFFRACTION100
1.7306-1.79990.17131260.14252639X-RAY DIFFRACTION100
1.7999-1.88190.1831200.14682643X-RAY DIFFRACTION100
1.8819-1.98110.14941290.14672619X-RAY DIFFRACTION100
1.9811-2.10520.1651490.14172608X-RAY DIFFRACTION100
2.1052-2.26780.17891570.14782607X-RAY DIFFRACTION100
2.2678-2.4960.16781590.15022616X-RAY DIFFRACTION100
2.496-2.85710.17421360.15682643X-RAY DIFFRACTION100
2.8571-3.59960.14731460.15252660X-RAY DIFFRACTION100
3.5996-60.08770.17821440.16252744X-RAY DIFFRACTION100

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