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- PDB-7u4i: Crystal structure of human GPX4-U46C-R152H in complex with CDS9 -

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Basic information

Entry
Database: PDB / ID: 7u4i
TitleCrystal structure of human GPX4-U46C-R152H in complex with CDS9
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 / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-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 / Biosynthesis of aspirin-triggered D-series resolvins / Biosynthesis of E-series 18(R)-resolvins / arachidonate metabolic process / 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
2-bromo-N-[(thiophen-2-yl)methyl]acetamide / THIOCYANATE ION / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 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
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
B: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3226
Polymers43,7382
Non-polymers5844
Water3,225179
1
A: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1613
Polymers21,8691
Non-polymers2922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1613
Polymers21,8691
Non-polymers2922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)137.108, 36.585, 84.050
Angle α, β, γ (deg.)90.000, 115.450, 90.000
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 21869.051 Da / Num. of mol.: 2 / 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-L9U / 2-bromo-N-[(thiophen-2-yl)methyl]acetamide


Mass: 234.114 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8BrNOS
#3: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CNS / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.18 Å3/Da / Density % sol: 43.47 %
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: 1.79→75.9 Å / Num. obs: 35852 / % possible obs: 99.5 % / Redundancy: 6.8 % / CC1/2: 0.994 / Rmerge(I) obs: 0.199 / Net I/σ(I): 7.1
Reflection shellResolution: 1.79→1.83 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.918 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2155 / CC1/2: 0.361 / % possible all: 99.7

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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: 1.97→75.9 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 31.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2458 2705 10.06 %
Rwork0.2007 24178 -
obs0.2054 26883 99.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 102.57 Å2 / Biso mean: 31.7419 Å2 / Biso min: 10.93 Å2
Refinement stepCycle: final / Resolution: 1.97→75.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2606 0 26 179 2811
Biso mean--63.7 41.36 -
Num. residues----323
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 19

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.97-2.010.3641500.30181257140799
2.01-2.040.33291460.27421255140199
2.04-2.090.31581450.24611254139999
2.09-2.130.30651340.22591249138399
2.13-2.180.27191400.22481256139699
2.18-2.240.27491480.22321267141599
2.24-2.30.26431220.220113051427100
2.3-2.360.2581350.211112621397100
2.36-2.440.31511420.2181256139898
2.44-2.530.26381260.20841256138299
2.53-2.630.27971380.199713101448100
2.63-2.750.25281490.208512551404100
2.75-2.890.28361530.203412451398100
2.89-3.070.24521420.193713101452100
3.07-3.310.26151340.202312901424100
3.31-3.640.22051360.187813051441100
3.64-4.170.19141440.1791271141599
4.17-5.260.21631690.16171258142797
5.26-75.90.20681520.19711317146997
Refinement TLS params.Method: refined / Origin x: -9.3097 Å / Origin y: -17.7977 Å / Origin z: 19.1315 Å
111213212223313233
T0.169 Å20.0568 Å2-0.013 Å2-0.1124 Å2-0.0464 Å2--0.2029 Å2
L0.6377 °20.0759 °20.0174 °2--0.4281 °2-0.1083 °2--0.1808 °2
S0.0677 Å °-0.0107 Å °-0.1124 Å °-0.0076 Å °-0.008 Å °0.0142 Å °0.0582 Å °-0.0073 Å °0.0301 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA7 - 170
2X-RAY DIFFRACTION1allB6 - 170
3X-RAY DIFFRACTION1allA201 - 202
4X-RAY DIFFRACTION1allB201 - 202
5X-RAY DIFFRACTION1allS1 - 179

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