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- PDB-7u4k: Crystal structure of human GPX4-U46C-R152H in complex with ML162 -

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Basic information

Entry
Database: PDB / ID: 7u4k
TitleCrystal structure of human GPX4-U46C-R152H in complex with ML162
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 / glutathione peroxidase / Synthesis of 5-eicosatetraenoic acids / lipoxygenase pathway / arachidonic acid metabolic process ...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 / glutathione peroxidase / Synthesis of 5-eicosatetraenoic acids / lipoxygenase pathway / arachidonic acid 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 / 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
Chem-L9C / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsForouhar, F. / Liu, H. / Lin, A.J. / Wang, Q. / Xia, X. / Soni, R.K. / 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4714
Polymers21,8691
Non-polymers6023
Water2,450136
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)82.565, 69.304, 32.983
Angle α, β, γ (deg.)90.000, 102.500, 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.: 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-L9C / 2-chloro-N-(3-chloro-4-methoxyphenyl)-N-[(1R)-2-oxo-2-[(2-phenylethyl)amino]-1-(thiophen-2-yl)ethyl]acetamide


Mass: 477.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22Cl2N2O3S
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 2.11 Å3/Da / Density % sol: 41.61 %
Crystal growTemperature: 291 K / Method: microbatch / pH: 6 / Details: 8% Tacsimate 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 X 16M / Detector: PIXEL / Date: Jun 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.59→52.55 Å / Num. obs: 23878 / % possible obs: 98.6 % / Redundancy: 6.7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.094 / Net I/σ(I): 11.6
Reflection shellResolution: 1.59→1.62 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.11 / Mean I/σ(I) obs: 1 / Num. unique obs: 1007 / CC1/2: 0.635 / % possible all: 84.1

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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: 1.69→52.55 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 20.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1811 1997 9.87 %
Rwork0.1528 18245 -
obs0.1556 20242 99.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.54 Å2 / Biso mean: 35.2649 Å2 / Biso min: 16.95 Å2
Refinement stepCycle: final / Resolution: 1.69→52.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1340 0 38 136 1514
Biso mean--92.92 45.66 -
Num. residues----166
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.69-1.730.2851540.2561326148099
1.73-1.780.23681170.21371273139099
1.78-1.830.20921380.18131339147799
1.83-1.890.20281440.17112581402100
1.89-1.960.18861410.16351313145499
1.96-2.040.21281550.15261273142899
2.04-2.130.20581280.15241307143599
2.13-2.240.18641370.154313281465100
2.24-2.380.19581360.146612891425100
2.38-2.570.1821420.152313191461100
2.57-2.820.17721410.16541301144299
2.82-3.230.20191500.15621290144099
3.23-4.070.15691470.13713131460100
4.07-52.550.15881670.14081316148399
Refinement TLS params.Method: refined / Origin x: 16.2804 Å / Origin y: -0.5052 Å / Origin z: 7.8531 Å
111213212223313233
T0.1965 Å2-0.0054 Å2-0.0087 Å2-0.2113 Å2-0.0091 Å2--0.2096 Å2
L1.0654 °2-0.3336 °2-0.1171 °2-1.3478 °2-0.3387 °2--1.8439 °2
S-0.0468 Å °-0.0192 Å °-0.0031 Å °0.0357 Å °0.0694 Å °0.0059 Å °-0.0152 Å °-0.0312 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA5 - 170
2X-RAY DIFFRACTION1allA201 - 203
3X-RAY DIFFRACTION1allS1 - 138

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