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- PDB-7u4m: Crystal structure of human GPX4-U46C in complex with LOC1886 -

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Basic information

Entry
Database: PDB / ID: 7u4m
TitleCrystal structure of human GPX4-U46C in complex with LOC1886
ComponentsPhospholipid hydroperoxide glutathione peroxidase
KeywordsOXIDOREDUCTASE / GPX4
Function / homology
Function and homology information


phospholipid-hydroperoxide glutathione peroxidase / phospholipid-hydroperoxide glutathione peroxidase activity / Synthesis of 15-eicosatetraenoic acid derivatives / Synthesis of 12-eicosatetraenoic acid derivatives / negative regulation of ferroptosis / selenium binding / Synthesis of 5-eicosatetraenoic acids / glutathione peroxidase / lipoxygenase pathway / Biosynthesis of aspirin-triggered D-series resolvins ...phospholipid-hydroperoxide glutathione peroxidase / phospholipid-hydroperoxide glutathione peroxidase activity / Synthesis of 15-eicosatetraenoic acid derivatives / Synthesis of 12-eicosatetraenoic acid derivatives / negative regulation of ferroptosis / selenium binding / Synthesis of 5-eicosatetraenoic acids / glutathione peroxidase / lipoxygenase pathway / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / arachidonic acid metabolic process / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins / glutathione peroxidase activity / long-chain fatty acid biosynthetic process / protein polymerization / phospholipid metabolic process / response to estradiol / chromatin organization / nuclear envelope / cellular response to oxidative stress / spermatogenesis / response to oxidative stress / protein-containing complex / mitochondrion / extracellular exosome / identical protein binding / nucleus / cytosol
Similarity search - Function
Glutathione peroxidase active site / Glutathione peroxidases active site. / Glutathione peroxidase / Glutathione peroxidase conserved site / Glutathione peroxidase / Glutathione peroxidases signature 2. / Glutathione peroxidase profile. / Thioredoxin-like superfamily
Similarity search - Domain/homology
4-methoxy-1H-indole-2-carbaldehyde / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsForouhar, F. / Liu, H. / Lin, A.J. / Wang, Q. / Polychronidou, V. / Soni, R.K. / Xia, X. / Stockwell, B.R.
Funding support United States, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P01CA87497 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R24GM141256 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM124165 United States
Department of Health & Human Services (HHS)OD021527 United States
Department of Energy (DOE, United States)DE-AC02-06CH11357 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35CA209896 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R61NS109407 United States
CitationJournal: Cell Chem Biol / Year: 2022
Title: Small-molecule allosteric inhibitors of GPX4.
Authors: Liu, H. / Forouhar, F. / Lin, A.J. / Wang, Q. / Polychronidou, V. / Soni, R.K. / Xia, X. / Stockwell, B.R.
History
DepositionFeb 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 28, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3014
Polymers21,8881
Non-polymers4123
Water2,432135
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, crystal packing
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.828, 115.654, 61.219
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-431-

HOH

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Components

#1: Protein Phospholipid hydroperoxide glutathione peroxidase / PHGPx / Glutathione peroxidase 4 / GSHPx-4


Mass: 21888.098 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPX4 / Production host: Escherichia coli (E. coli)
References: UniProt: P36969, phospholipid-hydroperoxide glutathione peroxidase
#2: Chemical ChemComp-LBI / 4-methoxy-1H-indole-2-carbaldehyde


Mass: 175.184 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H9NO2
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.74 Å3/Da / Density % sol: 55.15 %
Crystal growTemperature: 291 K / Method: microbatch / pH: 4.6
Details: 2 M sodium chloride and 0.1 M sodium acetate trihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.77→61.22 Å / Num. obs: 23683 / % possible obs: 99.1 % / Redundancy: 13.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.126 / Net I/σ(I): 11.4
Reflection shellResolution: 1.77→1.8 Å / Redundancy: 11.5 % / Rmerge(I) obs: 2.577 / Num. unique obs: 1140 / CC1/2: 0.4 / % possible all: 84.4

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7L8K

7l8k


Resolution: 1.93→58.51 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 20.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1971 1827 9.89 %
Rwork0.1611 16650 -
obs0.1646 18477 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 141.91 Å2 / Biso mean: 44.088 Å2 / Biso min: 21.73 Å2
Refinement stepCycle: final / Resolution: 1.93→58.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1374 0 30 135 1539
Biso mean--54.01 50.16 -
Num. residues----171
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.93-1.980.2651360.237312631399
1.98-2.040.23881300.201212591389
2.04-2.110.21861540.182312571411
2.11-2.180.2231220.171712691391
2.18-2.270.17581570.164612611418
2.27-2.370.1931010.151312851386
2.37-2.50.19791420.154712711413
2.5-2.650.23211530.167512641417
2.65-2.860.25541600.182812521412
2.86-3.150.19811640.16812631427
3.15-3.60.20281220.15913161438
3.6-4.540.17381520.130213021454
4.54-58.510.17211340.168113881522
Refinement TLS params.Method: refined / Origin x: -24.8516 Å / Origin y: 19.0661 Å / Origin z: -0.415 Å
111213212223313233
T0.2842 Å2-0.0459 Å20.0125 Å2-0.2661 Å20.0114 Å2--0.2371 Å2
L1.4416 °2-0.043 °20.0896 °2-1.5302 °2-0.1979 °2--1.4234 °2
S0.0529 Å °-0.0991 Å °0.0316 Å °0.2804 Å °-0.0899 Å °-0.1049 Å °-0.1185 Å °0.0248 Å °-0.7955 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA0 - 170
2X-RAY DIFFRACTION1allA201 - 203
3X-RAY DIFFRACTION1allS1 - 135

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