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- PDB-7u4n: Crystal structure of human GPX4-U46C in complex with RSL3 -

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Basic information

Entry
Database: PDB / ID: 7u4n
TitleCrystal structure of human GPX4-U46C in complex with RSL3
ComponentsPhospholipid hydroperoxide glutathione peroxidase
KeywordsOXIDOREDUCTASE / GPX4
Function / homology
Function and homology information


phospholipid-hydroperoxide glutathione peroxidase / phospholipid-hydroperoxide glutathione peroxidase activity / Synthesis of 12-eicosatetraenoic acid derivatives / Synthesis of 15-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 12-eicosatetraenoic acid derivatives / Synthesis of 15-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 / dendrite development / protein polymerization / phospholipid metabolic process / cerebellum development / multicellular organism growth / nuclear envelope / response to estradiol / chromatin organization / response to oxidative stress / spermatogenesis / response to lipopolysaccharide / apoptotic process / 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-L8X / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsForouhar, F. / Liu, H. / Lin, A.J. / Wang, Q. / Xia, X. / Soni, R.K. / Stockwell, B.R.
Funding support United States, 4items
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 Neurological Disorders and Stroke (NIH/NINDS)R61NS109407 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35CA209896 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 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification

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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)44,6584
Polymers43,7762
Non-polymers8822
Water9,080504
1
A: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3292
Polymers21,8881
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3292
Polymers21,8881
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)32.899, 92.856, 53.786
Angle α, β, γ (deg.)90.000, 100.190, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 21888.098 Da / Num. of mol.: 2 / Mutation: U46C
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-L8X / methyl (1S,3R)-2-(chloroacetyl)-1-[4-(methoxycarbonyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate


Mass: 440.876 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21ClN2O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 504 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.85 Å3/Da / Density % sol: 33.41 %
Crystal growTemperature: 291 K / Method: microbatch / pH: 7.5
Details: 0.1 M HEPES and 0.1 M magnesium nitrate hexahydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC HF-4M / Detector: PIXEL / Date: Oct 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.53→28.63 Å / Num. obs: 47272 / % possible obs: 98.4 % / Redundancy: 4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.051 / Net I/σ(I): 16
Reflection shellResolution: 1.53→1.57 Å / Rmerge(I) obs: 0.637 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 8621 / CC1/2: 0.668

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Processing

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

7l8k


Resolution: 1.6→26.72 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 17.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.188 4164 10.06 %
Rwork0.1497 37248 -
obs0.1535 41412 98.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 70.51 Å2 / Biso mean: 18.0077 Å2 / Biso min: 4.76 Å2
Refinement stepCycle: final / Resolution: 1.6→26.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2641 0 60 504 3205
Biso mean--30.74 32.14 -
Num. residues----328
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6-1.620.27011520.24371228138097
1.62-1.640.26691150.21871207132295
1.64-1.660.24851340.21661207134197
1.66-1.680.2351230.20621220134398
1.68-1.70.26121510.19411220137198
1.7-1.720.24341420.18891225136798
1.72-1.750.20071490.18281218136797
1.75-1.770.25451290.17531171130097
1.77-1.80.21191400.16221224136497
1.8-1.830.19421450.16071246139198
1.83-1.860.20711420.156912241366100
1.86-1.90.20251380.161312441382100
1.9-1.930.21311480.155912781426100
1.93-1.970.22861390.15112041343100
1.97-2.020.17521430.148712521395100
2.02-2.060.1681410.14112871428100
2.06-2.110.18391370.137512261363100
2.11-2.170.17021290.138212671396100
2.17-2.240.15971420.137912491391100
2.24-2.310.19521310.142812421373100
2.31-2.390.17241280.146512681396100
2.39-2.490.21931430.148312611404100
2.49-2.60.17341280.147212591387100
2.6-2.740.19361530.159112701423100
2.74-2.910.20971410.156812261367100
2.91-3.130.19451510.153412351386100
3.13-3.440.18941280.135912881416100
3.44-3.940.151480.1241244139299
3.94-4.960.13541300.116312781408100
4.96-26.720.17981440.15921280142499
Refinement TLS params.Method: refined / Origin x: 25.3216 Å / Origin y: -11.7515 Å / Origin z: -12.2808 Å
111213212223313233
T0.0535 Å2-0.0014 Å2-0.0072 Å2-0.054 Å20.0049 Å2--0.0534 Å2
L0.3357 °2-0.1536 °2-0.296 °2-0.1278 °20.1818 °2--0.3423 °2
S0.015 Å °0.003 Å °0.0203 Å °0.0064 Å °0.0067 Å °-0.0099 Å °0.0053 Å °-0.0002 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA8 - 170
2X-RAY DIFFRACTION1allB6 - 170
3X-RAY DIFFRACTION1allA201
4X-RAY DIFFRACTION1allB201
5X-RAY DIFFRACTION1allS1 - 504

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