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- PDB-8z32: Crystal Structure of HIF-PHD2 in complex with compound 3 -

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Basic information

Entry
Database: PDB / ID: 8z32
TitleCrystal Structure of HIF-PHD2 in complex with compound 3
ComponentsEgl nine homolog 1
KeywordsOXIDOREDUCTASE / Renal anemia / Inhibitor
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 / intracellular oxygen homeostasis / labyrinthine layer development / regulation protein catabolic process at postsynapse / 2-oxoglutarate-dependent dioxygenase activity / 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 / intracellular oxygen homeostasis / labyrinthine layer development / regulation protein catabolic process at postsynapse / 2-oxoglutarate-dependent dioxygenase activity / heart trabecula formation / regulation of modification of postsynaptic structure / cardiac muscle tissue morphogenesis / L-ascorbic acid binding / response to nitric oxide / ventricular septum morphogenesis / regulation of angiogenesis / regulation of neuron apoptotic process / negative regulation of DNA-binding transcription factor activity / 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 / 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. / MYND finger / Zinc finger MYND-type signature. / Zinc finger, MYND-type / Zinc finger MYND-type profile. / Oxoglutarate/iron-dependent dioxygenase / Fe(2+) 2-oxoglutarate dioxygenase domain profile.
Similarity search - Domain/homology
: / : / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsIto, S. / Baba, D. / Fukuda, T. / Tanaka, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2024
Title: Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.
Authors: Fukuda, T. / Kuribayashi, T. / Takano, R. / Sasaki, K. / Tsuji, T. / Niitsu, Y. / Ishii, K. / Hashimoto, M. / Baba, D. / Ito, S. / Tanaka, N.
History
DepositionApr 14, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Egl nine homolog 1
B: Egl nine homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,4166
Polymers55,6652
Non-polymers7504
Water1,08160
1
A: Egl nine homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,2083
Polymers27,8331
Non-polymers3752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-14 kcal/mol
Surface area10980 Å2
MethodPISA
2
B: Egl nine homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,2083
Polymers27,8331
Non-polymers3752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-14 kcal/mol
Surface area10710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.430, 67.743, 67.272
Angle α, β, γ (deg.)90.00, 116.36, 90.00
Int Tables number4
Space group name H-MP1211

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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 / Prolyl ...Hypoxia-inducible factor prolyl hydroxylase 2 / HIF-PH2 / HIF-prolyl hydroxylase 2 / HPH-2 / Prolyl hydroxylase domain-containing protein 2 / PHD2 / SM-20


Mass: 27832.674 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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
#2: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe
#3: Chemical ChemComp-A1L0V / 2-[[6-[(4-fluorophenyl)methyl]-2-methyl-5-oxidanyl-pyrimidin-4-yl]carbonylamino]ethanoic acid


Mass: 319.288 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H14FN3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.4 Å3/Da / Density % sol: 48.75 %
Crystal growTemperature: 295 K / Method: vapor diffusion
Details: Protein (30mg/ml in 20mM Tril-HCl (pH 7.5), 50mM NaCl), reservoir solution (1.3M ammonium sulfate, 20mM reduced glutathione, 2mM oxidized glutathione, 0.08M HEPES (pH 7.5))

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 6, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 17153 / % possible obs: 94.2 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.094 / Χ2: 0.885 / Net I/av σ(I): 13 / Net I/σ(I): 9.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsΧ2% possible all
2.5-2.563.30.40428900.675.2
2.56-2.623.30.3829590.62379.1
2.62-2.693.40.3510350.58585.6
2.69-2.773.50.31910960.65191.8
2.77-2.863.60.28211500.66895.6
2.86-2.963.70.2411740.68697.3
2.96-3.083.70.19711920.68598.1
3.08-3.223.80.17312030.74998.8
3.22-3.393.80.14211850.82198.8
3.39-3.613.80.10911980.9798.4
3.61-3.883.70.08912061.02498.7
3.88-4.273.70.07111961.15198.8
4.27-4.893.70.05712001.23898
4.89-6.163.70.05412181.06698.9
6.16-503.50.06112511.46498.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
HKL-2000data scaling
HKL-2000data reduction
PHASER1.3.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.927 / SU B: 25.495 / SU ML: 0.26 / Cross valid method: THROUGHOUT / ESU R: 0.742 / ESU R Free: 0.305 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.24508 1667 9.7 %RANDOM
Rwork0.2052 ---
obs0.20906 15438 93.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 58.696 Å2
Baniso -1Baniso -2Baniso -3
1--0.48 Å2-0 Å2-3 Å2
2---0.49 Å2-0 Å2
3---2.64 Å2
Refinement stepCycle: 1 / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3295 0 48 60 3403
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0123420
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.8741.6574616
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3945412
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.933530
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.46210579
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0750.2481
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022597
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2545.7021660
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.84810.2382068
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.8875.9361760
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.03165.25139
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
681medium positional0.210.5
692tight thermal4.580.5
681medium thermal4.942
LS refinement shellResolution: 2.502→2.566 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 92 -
Rwork0.305 788 -
obs--67.23 %
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)
10.9138-0.1845-0.06670.68540.11511.1273-0.0028-0.0006-0.01490.04120.0371-0.0010.04220.0845-0.03420.23460.0237-0.15110.0318-0.02480.1028-1.2535-6.4555-17.893
20.9392-0.38720.17641.1642-0.00481.12860.007-0.03690.0274-0.0099-0.0060.0282-0.0414-0.0249-0.00090.1853-0.0069-0.11050.0185-0.00090.0701-27.21116.5793-5.0164
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A188 - 501
2X-RAY DIFFRACTION2B188 - 501

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