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- PDB-9fsn: FIH in complex with Enarodustat crystal structure at 2.2A -

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Basic information

Entry
Database: PDB / ID: 9fsn
TitleFIH in complex with Enarodustat crystal structure at 2.2A
ComponentsHypoxia-inducible factor 1-alpha inhibitor
KeywordsOXIDOREDUCTASE / FIH / oxygenase / Complex / inhibitor
Function / homology
Function and homology information


hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / regulation of vascular endothelial growth factor receptor signaling pathway / Cellular response to hypoxia / positive regulation of vasculogenesis / carboxylic acid binding / ankyrin repeat binding ...hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / regulation of vascular endothelial growth factor receptor signaling pathway / Cellular response to hypoxia / positive regulation of vasculogenesis / carboxylic acid binding / ankyrin repeat binding / Notch binding / oxygen sensor activity / negative regulation of Notch signaling pathway / NF-kappaB binding / positive regulation of myoblast differentiation / ferrous iron binding / transcription corepressor activity / RNA polymerase II-specific DNA-binding transcription factor binding / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / zinc ion binding / nucleoplasm / cytosol / cytoplasm
Similarity search - Function
Hypoxia-inducible factor 1-alpha inhibitor, domain II / Cupin-like domain 8 / Cupin-like domain / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / RmlC-like jelly roll fold
Similarity search - Domain/homology
: / : / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsCorner, T. / Brewitz, L. / Kaur, S. / Schnaubelt, L.I. / Allen, M.D. / Schofield, C.J.
Funding support United Kingdom, 4items
OrganizationGrant numberCountry
Wellcome Trust106244/Z/14/Z United Kingdom
Cancer Research UKC8717/A18245 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/J003018/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R000344/1 United Kingdom
CitationJournal: Chemmedchem / Year: 2024
Title: Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat.
Authors: Corner, T.P. / Salah, E. / Tumber, A. / Kaur, S. / Nakashima, Y. / Allen, M.D. / Schnaubelt, L.I. / Fiorini, G. / Brewitz, L. / Schofield, C.J.
History
DepositionJun 21, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8113
Polymers40,4151
Non-polymers3952
Water1,15364
1
A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules

A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,6216
Polymers80,8312
Non-polymers7914
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area3460 Å2
ΔGint-36 kcal/mol
Surface area30940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.450, 86.450, 147.220
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-545-

HOH

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Components

#1: Protein Hypoxia-inducible factor 1-alpha inhibitor / Factor inhibiting HIF-1 / FIH-1 / Hypoxia-inducible factor asparagine hydroxylase


Mass: 40415.355 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The first residues were not observed in the electron density
Source: (gene. exp.) Homo sapiens (human) / Gene: HIF1AN, FIH1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): C41
References: UniProt: Q9NWT6, hypoxia-inducible factor-asparagine dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one ...References: UniProt: Q9NWT6, hypoxia-inducible factor-asparagine 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-A1IF7 / Enarodustat / 2-[[7-oxidanylidene-5-(2-phenylethyl)-3H-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbonylamino]ethanoic acid


Mass: 340.333 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16N4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 64 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.4 Å3/Da / Density % sol: 63.86 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Morpheus 1, well C1, 0.09 M NPS, 0.1 M Buffer System 1 pH 6.5, 30 % Precipitant Mix 1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97628 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 18, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97628 Å / Relative weight: 1
ReflectionResolution: 2.2→56.05 Å / Num. obs: 29152 / % possible obs: 100 % / Redundancy: 26.6 % / Biso Wilson estimate: 55.98 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.017 / Rrim(I) all: 0.063 / Net I/σ(I): 28.7
Reflection shellResolution: 2.2→2.27 Å / Rmerge(I) obs: 1.385 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 2474 / CC1/2: 0.899 / Rpim(I) all: 0.373 / Rrim(I) all: 1.434

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4B7K

4b7k


Resolution: 2.2→43.22 Å / SU ML: 0.2433 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.3241
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2082 2708 5.01 %
Rwork0.1971 51384 -
obs0.1977 27056 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.3 Å2
Refinement stepCycle: LAST / Resolution: 2.2→43.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2770 0 26 64 2860
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00232898
X-RAY DIFFRACTIONf_angle_d0.52893938
X-RAY DIFFRACTIONf_chiral_restr0.0424390
X-RAY DIFFRACTIONf_plane_restr0.0049526
X-RAY DIFFRACTIONf_dihedral_angle_d16.23241093
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.240.32511490.29012686X-RAY DIFFRACTION99.96
2.24-2.280.28771500.27042720X-RAY DIFFRACTION99.97
2.28-2.330.26061140.24742733X-RAY DIFFRACTION100
2.33-2.380.22431370.22662690X-RAY DIFFRACTION99.89
2.38-2.440.23661260.21442696X-RAY DIFFRACTION99.86
2.44-2.50.23021630.21272697X-RAY DIFFRACTION100
2.5-2.560.231410.21822713X-RAY DIFFRACTION99.96
2.56-2.640.23611350.23372710X-RAY DIFFRACTION100
2.64-2.720.26081350.24722724X-RAY DIFFRACTION100
2.72-2.820.28681730.24072671X-RAY DIFFRACTION99.93
2.82-2.940.23191430.24232696X-RAY DIFFRACTION99.96
2.94-3.070.2611210.22712742X-RAY DIFFRACTION100
3.07-3.230.27271560.23662676X-RAY DIFFRACTION100
3.23-3.430.22171170.23332733X-RAY DIFFRACTION100
3.43-3.70.21811400.19872717X-RAY DIFFRACTION100
3.7-4.070.19691360.19032711X-RAY DIFFRACTION100
4.07-4.660.13841610.15132684X-RAY DIFFRACTION100
4.66-5.860.21091820.16962666X-RAY DIFFRACTION100
5.87-43.220.17821290.17232719X-RAY DIFFRACTION99.79
Refinement TLS params.Method: refined / Origin x: -16.1062572113 Å / Origin y: 21.4955150081 Å / Origin z: -8.91109636408 Å
111213212223313233
T0.407568982882 Å20.000316126648892 Å20.04323258226 Å2-0.523727175288 Å20.0640653711831 Å2--0.496500947123 Å2
L2.84962243061 °2-1.16993021633 °21.49492309345 °2-1.65699194648 °2-0.809815241994 °2--1.85301312601 °2
S0.011601481297 Å °-0.123622647305 Å °0.193910981098 Å °0.161422531733 Å °0.0118294669926 Å °0.0697969528858 Å °-0.119882776951 Å °-0.252247861649 Å °-0.00974794998895 Å °
Refinement TLS groupSelection details: chain A

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