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- PDB-7u4l: Crystal structure of human GPX4-U46C in complex with MAC-5576 -

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Basic information

Entry
Database: PDB / ID: 7u4l
TitleCrystal structure of human GPX4-U46C in complex with MAC-5576
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 / 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
thiophene-2-carbaldehyde / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsForouhar, F. / Liu, H. / Lin, A.J. / Wang, Q. / Polychronidou, V. / Soni, R.K. / Xia, X. / Stockwell, B.R.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P01CA87497 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 Energy (DOE, United States)DE-AC02-06CH11357 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

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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
C: Phospholipid hydroperoxide glutathione peroxidase
D: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,45012
Polymers87,5524
Non-polymers8978
Water6,503361
1
A: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1123
Polymers21,8881
Non-polymers2242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1123
Polymers21,8881
Non-polymers2242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1123
Polymers21,8881
Non-polymers2242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Phospholipid hydroperoxide glutathione peroxidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,1123
Polymers21,8881
Non-polymers2242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.889, 91.506, 72.189
Angle α, β, γ (deg.)90.000, 90.000, 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.: 4
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-LW1 / thiophene-2-carbaldehyde / Thiophene-2-carboxaldehyde


Mass: 112.150 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C5H4OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 361 / 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: 2.3 Å3/Da / Density % sol: 46.45 %
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: Oct 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.85→91.51 Å / Num. obs: 67235 / % possible obs: 99.7 % / Redundancy: 7 % / CC1/2: 0.989 / Rmerge(I) obs: 0.197 / Net I/σ(I): 2.4
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 7.2 % / Rmerge(I) obs: 2.083 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 4076 / CC1/2: 0.34 / % possible all: 99.2

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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: 2.25→72.19 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.4 / Phase error: 23.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2299 3701 9.86 %
Rwork0.1634 33832 -
obs0.17 37533 99.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 102.5 Å2 / Biso mean: 34.2225 Å2 / Biso min: 5.82 Å2
Refinement stepCycle: final / Resolution: 2.25→72.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5331 0 56 361 5748
Biso mean--57.8 39.65 -
Num. residues----661
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 26

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.25-2.280.29341270.207612711398100
2.28-2.310.31331140.192913381452100
2.31-2.340.24681240.198113341458100
2.34-2.380.24811590.185712571416100
2.38-2.420.29091300.177113021432100
2.42-2.460.28781540.190612671421100
2.46-2.50.25721140.185113381452100
2.5-2.540.26711480.187913131461100
2.54-2.590.25791720.182912521424100
2.59-2.650.28041500.182112931443100
2.65-2.70.26111290.177713201449100
2.7-2.770.29121470.188113131460100
2.77-2.830.2851470.195112631410100
2.83-2.910.26781680.197112801448100
2.91-30.28141460.177912931439100
3-3.090.23041230.18311279140299
3.09-3.20.23561390.173913091448100
3.2-3.330.27461600.170813041464100
3.33-3.480.25391210.169513131434100
3.48-3.670.20331520.152113091461100
3.67-3.90.23021270.15311295142299
3.9-4.20.18151390.142313311470100
4.2-4.620.17981670.119612901457100
4.62-5.290.18821730.138412881461100
5.29-6.660.19321560.14611292144899
6.67-72.190.17331150.150913881503100
Refinement TLS params.Method: refined / Origin x: 38.6612 Å / Origin y: -6.0321 Å / Origin z: 9.996 Å
111213212223313233
T0.0775 Å2-0.0167 Å2-0.0028 Å2-0.0571 Å20.007 Å2--0.0775 Å2
L0.4728 °2-0.2174 °2-0.041 °2-0.252 °20.1125 °2--0.0844 °2
S0.0253 Å °0.0237 Å °-0.0397 Å °-0.0343 Å °-0.0104 Å °-0.0077 Å °-0.0157 Å °0.0398 Å °-0.0129 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA6 - 170
2X-RAY DIFFRACTION1allB5 - 170
3X-RAY DIFFRACTION1allC6 - 170
4X-RAY DIFFRACTION1allD6 - 170
5X-RAY DIFFRACTION1allA201 - 202
6X-RAY DIFFRACTION1allB201 - 202
7X-RAY DIFFRACTION1allC201 - 202
8X-RAY DIFFRACTION1allD201 - 202
9X-RAY DIFFRACTION1allS1 - 361

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