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- PDB-6hkq: Human GPX4 in complex with covalent Inhibitor ML162 (S enantiomer) -

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Basic information

Entry
Database: PDB / ID: 6hkq
TitleHuman GPX4 in complex with covalent Inhibitor ML162 (S enantiomer)
ComponentsPhospholipid hydroperoxide glutathione peroxidase
KeywordsOXIDOREDUCTASE / ANTI-OXIDATVE DEFENSE SYSTEM / Covalent inhibitor
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. / Glutaredoxin / Glutaredoxin / Thioredoxin-like superfamily ...Glutathione peroxidase active site / Glutathione peroxidases active site. / Glutathione peroxidase / Glutathione peroxidase conserved site / Glutathione peroxidase / Glutathione peroxidases signature 2. / Glutathione peroxidase profile. / Glutaredoxin / Glutaredoxin / Thioredoxin-like superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-G9N / Phospholipid hydroperoxide glutathione peroxidase GPX4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsHillig, R.C. / Moosmayer, D. / Hilpmann, A. / Hoffmann, L. / Schnirch, L. / Eaton, J.K. / Badock, V. / Gradl, S.
CitationJournal: Acta Crystallogr D Struct Biol / Year: 2021
Title: Crystal structures of the selenoprotein glutathione peroxidase 4 in its apo form and in complex with the covalently bound inhibitor ML162.
Authors: Moosmayer, D. / Hilpmann, A. / Hoffmann, J. / Schnirch, L. / Zimmermann, K. / Badock, V. / Furst, L. / Eaton, J.K. / Viswanathan, V.S. / Schreiber, S.L. / Gradl, S. / Hillig, R.C.
History
DepositionSep 7, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 16, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 7, 2022Group: Advisory / Database references ...Advisory / Database references / Derived calculations / Source and taxonomy
Category: database_2 / entity_src_gen ...database_2 / entity_src_gen / pdbx_unobs_or_zero_occ_atoms / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.gene_src_common_name

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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)21,1586
Polymers20,3661
Non-polymers7925
Water4,089227
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area660 Å2
ΔGint-13 kcal/mol
Surface area8640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)32.734, 57.249, 81.311
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 20366.230 Da / Num. of mol.: 1 / Mutation: C66S
Source method: isolated from a genetically manipulated source
Details: C-terminal hexa-His tag added for affinity chromatography
Source: (gene. exp.) Homo sapiens (human) / Gene: GPX4 / Production host: Escherichia coli (E. coli)
References: UniProt: P36969, phospholipid-hydroperoxide glutathione peroxidase

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Non-polymers , 5 types, 232 molecules

#2: Chemical ChemComp-G9N / (2~{S})-2-[2-chloranylethanoyl-(3-chloranyl-4-methoxy-phenyl)amino]-~{N}-(2-phenylethyl)-2-thiophen-2-yl-ethanamide


Mass: 477.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22Cl2N2O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 227 / Source method: isolated from a natural source / Formula: H2O

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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: 1.87 Å3/Da / Density % sol: 34.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: Reservoir made from 0.2 M ammonium sulfate, 20% (w/v) PEG 3350. Prio to crystal set-up, the protein was modified with covalent inhibitor, purified via gelfiltration and concentrated to 13.5 ...Details: Reservoir made from 0.2 M ammonium sulfate, 20% (w/v) PEG 3350. Prio to crystal set-up, the protein was modified with covalent inhibitor, purified via gelfiltration and concentrated to 13.5 mg/ml in 50 mM TrisHCl pH 8.0, 150 mM NaCl, 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Mar 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.54→46.81 Å / Num. obs: 20009 / % possible obs: 86.6 % / Redundancy: 10.5 % / Rpim(I) all: 0.03 / Rrim(I) all: 0.11 / Rsym value: 0.1 / Net I/σ(I): 20.2
Reflection shellResolution: 1.54→1.59 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 1092 / CC1/2: 0.81 / Rpim(I) all: 0.33 / Rrim(I) all: 0.97 / Rsym value: 0.9 / % possible all: 72.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.54→46.81 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.902 / SU ML: 0.052 / Cross valid method: THROUGHOUT / ESU R: 0.09 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18416 951 4.8 %RANDOM
Rwork0.1495 ---
obs0.15116 19002 86.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.524 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å2-0 Å2-0 Å2
2---0.13 Å20 Å2
3---0.19 Å2
Refinement stepCycle: 1 / Resolution: 1.54→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1339 0 47 228 1614
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0191459
X-RAY DIFFRACTIONr_bond_other_d0.0020.021323
X-RAY DIFFRACTIONr_angle_refined_deg1.7011.9671970
X-RAY DIFFRACTIONr_angle_other_deg1.0233.0033051
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0915.056178
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.87624.57170
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.91715244
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.775156
X-RAY DIFFRACTIONr_chiral_restr0.110.2200
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211647
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02303
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.6671.262678
X-RAY DIFFRACTIONr_mcbond_other1.6191.257677
X-RAY DIFFRACTIONr_mcangle_it2.6182.837850
X-RAY DIFFRACTIONr_mcangle_other2.6312.843851
X-RAY DIFFRACTIONr_scbond_it3.1291.673781
X-RAY DIFFRACTIONr_scbond_other3.1271.675782
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4963.5391116
X-RAY DIFFRACTIONr_long_range_B_refined7.31218.2211727
X-RAY DIFFRACTIONr_long_range_B_other7.14317.1561661
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.544→1.584 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 70 -
Rwork0.226 1089 -
obs--68.87 %
Refinement TLS params.Method: refined / Origin x: -9.371 Å / Origin y: -0.577 Å / Origin z: 10.245 Å
111213212223313233
T0.0254 Å20.0016 Å2-0.0008 Å2-0.0217 Å2-0.0001 Å2--0.008 Å2
L0.4698 °2-0.0049 °20.2013 °2-0.2464 °2-0.0668 °2--0.3053 °2
S-0.0039 Å °-0.0192 Å °0.0235 Å °-0.0064 Å °0.0003 Å °-0.002 Å °0.0049 Å °-0.0139 Å °0.0036 Å °

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