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- PDB-7u4j: Crystal structure of human GPX4-U46C-R152H in complex with TMT10 -

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Basic information

Entry
Database: PDB / ID: 7u4j
TitleCrystal structure of human GPX4-U46C-R152H in complex with TMT10
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 / selenium binding / Synthesis of 5-eicosatetraenoic acids / glutathione peroxidase / lipoxygenase pathway / arachidonate metabolic process / 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 / selenium binding / Synthesis of 5-eicosatetraenoic acids / glutathione peroxidase / lipoxygenase pathway / arachidonate metabolic process / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / Biosynthesis of D-series resolvins / Biosynthesis of E-series 18(S)-resolvins / glutathione peroxidase activity / long-chain fatty acid biosynthetic process / negative regulation of ferroptosis / protein polymerization / phospholipid metabolic process / response to estradiol / nuclear envelope / chromatin organization / 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
~{N}-(3-chloranyl-4-methoxy-phenyl)ethanamide / THIOCYANATE ION / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 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 Cancer Institute (NIH/NCI)R35CA209896 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R61NS109407 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
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
Revision 1.3Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)22,1273
Polymers21,8691
Non-polymers2582
Water2,864159
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)128.095, 36.568, 42.180
Angle α, β, γ (deg.)90.000, 101.300, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-454-

HOH

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Components

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


Mass: 21869.051 Da / Num. of mol.: 1 / Mutation: U46C, R152H
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-8NB / ~{N}-(3-chloranyl-4-methoxy-phenyl)ethanamide


Mass: 199.634 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H10ClNO2
#3: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.21 Å3/Da / Density % sol: 44.47 %
Crystal growTemperature: 291 K / Method: microbatch / pH: 7 / Details: 0.2 M potassium thiocyanate and 20% (w/v) PEG 3350

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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 S 16M / Detector: PIXEL / Date: Sep 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.62→41.36 Å / Num. obs: 23632 / % possible obs: 95.5 % / Redundancy: 6.8 % / CC1/2: 0.989 / Rmerge(I) obs: 0.265 / Net I/σ(I): 7.3
Reflection shellResolution: 1.62→1.65 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.711 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 464 / CC1/2: 0.324 / % possible all: 38.3

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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: 7L8L

7l8l


Resolution: 1.81→41.36 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 22.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2051 1692 9.68 %
Rwork0.1703 15794 -
obs0.1738 17486 98.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 86.92 Å2 / Biso mean: 25.2478 Å2 / Biso min: 5.49 Å2
Refinement stepCycle: final / Resolution: 1.81→41.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1308 0 16 159 1483
Biso mean--35.37 40.81 -
Num. residues----162
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.81-1.860.27731580.24051278143698
1.86-1.920.27991360.20781288142496
1.92-1.990.24521310.196813111442100
1.99-2.070.22431210.18281308142998
2.07-2.170.2221400.16421316145698
2.17-2.280.20891490.16281292144199
2.28-2.420.1961380.15621333147199
2.42-2.610.21121410.16551311145299
2.61-2.870.19671430.18121314145799
2.87-3.290.18911400.164413451485100
3.29-4.140.19181530.15011322147599
4.14-41.360.18831420.17281376151898
Refinement TLS params.Method: refined / Origin x: 19.1127 Å / Origin y: -0.3643 Å / Origin z: 5.6072 Å
111213212223313233
T0.1064 Å2-0.0025 Å2-0.0041 Å2-0.0662 Å2-0.0024 Å2--0.0721 Å2
L0.6441 °20.2911 °2-0.0058 °2-1.2627 °20.1135 °2--0.4394 °2
S0.0188 Å °0.0084 Å °0.0558 Å °0.0833 Å °-0.0678 Å °0.3139 Å °-0.0339 Å °0.0254 Å °-0.1634 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA7 - 170
2X-RAY DIFFRACTION1allA201 - 202
3X-RAY DIFFRACTION1allS1 - 160

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