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- PDB-9i4h: Factor Inhibiting HIF (FIH) in complex with manganese and 3-Hydro... -

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Basic information

Entry
Database: PDB / ID: 9i4h
TitleFactor Inhibiting HIF (FIH) in complex with manganese and 3-Hydroxy-5-(3-(4-(hydroxymethyl)-3-nitrophenyl)isoxazol-5-yl)picolinoyl)glycine
ComponentsHypoxia-inducible factor 1-alpha inhibitor
KeywordsOXIDOREDUCTASE / Hypoxia-inducible factor 1-alpha inhibitor / Factor inhibiting HIF (FIH)
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 / carboxylic acid binding / positive regulation of vasculogenesis / 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 / carboxylic acid binding / positive regulation of vasculogenesis / 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 / perinuclear region of cytoplasm / 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: 2.3 Å
AuthorsKaur, S. / Zhang, X.J. / Schofield, C.J.
Funding support United Kingdom, China, 2items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/L009846/1 United Kingdom
National Natural Science Foundation of China (NSFC)No. 82322062 (Medicinal chemistry) China
CitationJournal: J.Am.Chem.Soc. / Year: 2025
Title: Light-Induced, Lysine-Targeting Irreversible Covalent Inhibition of the Human Oxygen Sensing Hydroxylase Factor Inhibiting HIF (FIH).
Authors: Wu, Y. / Li, Z. / Kaur, S. / Zhang, Z. / Yue, J. / Tumber, A. / Zhang, H. / Song, Z. / Yang, P. / Dong, Y. / Yang, F. / Li, X. / Schofield, C.J. / Zhang, X.
History
DepositionJan 24, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 21, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 11, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)40,8853
Polymers40,4151
Non-polymers4692
Water1,18966
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)81,7696
Polymers80,8312
Non-polymers9394
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_465y-1,x+1,-z1
Buried area4930 Å2
ΔGint-36 kcal/mol
Surface area31240 Å2
Unit cell
Length a, b, c (Å)86.028, 86.028, 147.495
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-535-

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 residues missing are unstructured / 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-A1IZ5 / 2-[[5-[3-[4-(hydroxymethyl)-3-nitro-phenyl]-1,2-oxazol-5-yl]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic acid


Mass: 414.326 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N4O8 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 3.38 Å3/Da / Density % sol: 63.57 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: Morpheus C5 0.09 M NPS 0.1 M Buffer System 2 7.5 30 % v/v Precipitant Mix 2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97627 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 13, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97627 Å / Relative weight: 1
ReflectionResolution: 2.3→60.84 Å / Num. obs: 25421 / % possible obs: 99.9 % / Redundancy: 26.3 % / Biso Wilson estimate: 61.2 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.116 / Rpim(I) all: 0.023 / Rrim(I) all: 0.118 / Net I/σ(I): 18
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 25.8 % / Rmerge(I) obs: 2.084 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 2433 / CC1/2: 0.784 / Rpim(I) all: 0.413 / Rrim(I) all: 2.125 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→60.83 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2177 1213 4.79 %
Rwork0.2034 --
obs0.2041 25333 99.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→60.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2766 0 31 66 2863
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004
X-RAY DIFFRACTIONf_angle_d0.695
X-RAY DIFFRACTIONf_dihedral_angle_d21.6271092
X-RAY DIFFRACTIONf_chiral_restr0.083389
X-RAY DIFFRACTIONf_plane_restr0.006524
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.390.28071390.26672603X-RAY DIFFRACTION100
2.39-2.50.27571170.24482635X-RAY DIFFRACTION100
2.5-2.630.32651520.23812615X-RAY DIFFRACTION100
2.63-2.80.25071290.25062645X-RAY DIFFRACTION100
2.8-3.010.30281250.27212652X-RAY DIFFRACTION100
3.01-3.320.25551440.24852665X-RAY DIFFRACTION100
3.32-3.80.21271410.21672682X-RAY DIFFRACTION100
3.8-4.780.17341360.1652727X-RAY DIFFRACTION100
4.78-60.830.19471300.17712896X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -27.0017 Å / Origin y: 21.783 Å / Origin z: -8.8133 Å
111213212223313233
T0.3959 Å2-0.0066 Å2-0.0462 Å2-0.5292 Å2-0.0741 Å2--0.4986 Å2
L2.8573 °2-1.2967 °2-1.7756 °2-1.2407 °20.8246 °2--1.6652 °2
S0.0009 Å °-0.0594 Å °-0.1125 Å °0.1949 Å °0.0122 Å °-0.0592 Å °0.1272 Å °0.2133 Å °-0.0133 Å °
Refinement TLS groupSelection details: chain A

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