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- PDB-6llx: Discovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Mali... -

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Basic information

Entry
Database: PDB / ID: 6llx
TitleDiscovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Malignant Glioblastoma
ComponentsGlutathione S-transferase P
KeywordsTRANSFERASE / Oxidative stress / NQO1 / GSTP1 / GBM / small molecular inhibitor
Function / homology
Function and homology information


nitric oxide storage / S-nitrosoglutathione binding / kinase regulator activity / negative regulation of biosynthetic process / TRAF2-GSTP1 complex / dinitrosyl-iron complex binding / common myeloid progenitor cell proliferation / hepoxilin biosynthetic process / glutathione derivative biosynthetic process / negative regulation of nitric-oxide synthase biosynthetic process ...nitric oxide storage / S-nitrosoglutathione binding / kinase regulator activity / negative regulation of biosynthetic process / TRAF2-GSTP1 complex / dinitrosyl-iron complex binding / common myeloid progenitor cell proliferation / hepoxilin biosynthetic process / glutathione derivative biosynthetic process / negative regulation of nitric-oxide synthase biosynthetic process / negative regulation of JUN kinase activity / nitric oxide binding / linoleic acid metabolic process / negative regulation of leukocyte proliferation / Glutathione conjugation / negative regulation of monocyte chemotactic protein-1 production / Paracetamol ADME / JUN kinase binding / glutathione peroxidase activity / negative regulation of stress-activated MAPK cascade / negative regulation of interleukin-1 beta production / regulation of stress-activated MAPK cascade / prostaglandin metabolic process / negative regulation of MAPK cascade / Detoxification of Reactive Oxygen Species / glutathione transferase / negative regulation of acute inflammatory response / glutathione transferase activity / negative regulation of tumor necrosis factor production / negative regulation of tumor necrosis factor-mediated signaling pathway / glutathione metabolic process / negative regulation of canonical NF-kappaB signal transduction / negative regulation of fibroblast proliferation / xenobiotic metabolic process / regulation of ERK1 and ERK2 cascade / response to reactive oxygen species / positive regulation of superoxide anion generation / negative regulation of MAP kinase activity / central nervous system development / fatty acid binding / negative regulation of extrinsic apoptotic signaling pathway / negative regulation of protein kinase activity / negative regulation of ERK1 and ERK2 cascade / secretory granule lumen / cellular response to lipopolysaccharide / vesicle / ficolin-1-rich granule lumen / Neutrophil degranulation / negative regulation of apoptotic process / mitochondrion / extracellular space / extracellular exosome / extracellular region / nucleus / cytosol / cytoplasm
Similarity search - Function
Glutathione S-transferase, Pi class / Glutathione S-transferase, C-terminal domain / Glutathione S-transferase, N-terminal domain / Glutathione transferase family / Glutathione S-transferase, C-terminal / Soluble glutathione S-transferase N-terminal domain profile. / Glutathione S-transferase, C-terminal-like / Soluble glutathione S-transferase C-terminal domain profile. / Glutathione S-transferase, N-terminal / Glutathione S-transferase, C-terminal domain superfamily / Thioredoxin-like superfamily
Similarity search - Domain/homology
GLUTATHIONE / Glutathione S-transferase P
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.581 Å
AuthorsYe, K. / Li, H. / Lei, K.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)RO1 CA186918 United States
CitationJournal: J Hematol Oncol / Year: 2020
Title: Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.
Authors: Lei, K. / Gu, X. / Alvarado, A.G. / Du, Y. / Luo, S. / Ahn, E.H. / Kang, S.S. / Ji, B. / Liu, X. / Mao, H. / Fu, H. / Kornblum, H.I. / Jin, L. / Li, H. / Ye, K.
History
DepositionDec 24, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Glutathione S-transferase P
B: Glutathione S-transferase P
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,7906
Polymers47,7852
Non-polymers1,0054
Water7,674426
1
A: Glutathione S-transferase P
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3953
Polymers23,8921
Non-polymers5032
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area610 Å2
ΔGint-1 kcal/mol
Surface area10050 Å2
MethodPISA
2
B: Glutathione S-transferase P
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3953
Polymers23,8921
Non-polymers5032
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area610 Å2
ΔGint-2 kcal/mol
Surface area10490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.655, 82.179, 89.324
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Glutathione S-transferase P / GST class-pi / GSTP1-1


Mass: 23892.346 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSTP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09211, glutathione transferase
#2: Chemical ChemComp-GSH / GLUTATHIONE / Glutathione


Mass: 307.323 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N3O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 426 / 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: 2.71 Å3/Da / Density % sol: 54.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1M MES PH5.8 ,30% PEG6000 ,10mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9789 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Nov 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9789 Å / Relative weight: 1
ReflectionResolution: 1.58→50 Å / Num. obs: 70461 / % possible obs: 99.7 % / Redundancy: 5.4 % / Biso Wilson estimate: 9.38 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.053 / Rrim(I) all: 0.118 / Rsym value: 0.094 / Net I/σ(I): 32.61
Reflection shellResolution: 1.58→1.61 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.213 / Num. unique obs: 3455 / CC1/2: 0.952 / Rpim(I) all: 0.104 / Rrim(I) all: 0.238 / Rsym value: 0.238 / % possible all: 99.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3gus

3gus


Resolution: 1.581→24.11 Å / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.6
RfactorNum. reflection% reflection
Rfree0.2229 2000 2.84 %
Rwork0.2001 --
obs0.2007 70364 99.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 44.81 Å2 / Biso mean: 11.7893 Å2 / Biso min: 2.77 Å2
Refinement stepCycle: final / Resolution: 1.581→24.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3319 0 4 426 3749
Biso mean--15.99 21 -
Num. residues----424
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5812-1.62070.22691340.182477298
1.6207-1.66460.23041470.17534833100
1.6646-1.71350.18241510.17744810100
1.7135-1.76880.21781240.17544867100
1.7688-1.8320.23771490.19174864100
1.832-1.90530.2151450.19634812100
1.9053-1.9920.24681390.20824912100
1.992-2.0970.2461440.20934856100
2.097-2.22830.21791310.20654865100
2.2283-2.40020.21141450.20214907100
2.4002-2.64150.241430.20844914100
2.6415-3.02310.24271500.2164489799
3.0231-3.80630.20121460.20384960100
3.8063-24.110.21941520.1951509598

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