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

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Basic information

Entry
Database: PDB / ID: 6llc
TitleDiscovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Malignant Glioblastoma
ComponentsNAD(P)H dehydrogenase [quinone] 1
KeywordsOXIDOREDUCTASE / Oxidative stress / GBM / small molecular inhibitor
Function / homology
Function and homology information


ubiquinone metabolic process / vitamin E metabolic process / NAD(P)H dehydrogenase (quinone) / NADPH dehydrogenase (quinone) activity / vitamin K metabolic process / cytochrome-b5 reductase activity, acting on NAD(P)H / NADH dehydrogenase (quinone) (non-electrogenic) activity / NAD(P)H dehydrogenase (quinone) activity / synaptic transmission, cholinergic / Regulation of ornithine decarboxylase (ODC) ...ubiquinone metabolic process / vitamin E metabolic process / NAD(P)H dehydrogenase (quinone) / NADPH dehydrogenase (quinone) activity / vitamin K metabolic process / cytochrome-b5 reductase activity, acting on NAD(P)H / NADH dehydrogenase (quinone) (non-electrogenic) activity / NAD(P)H dehydrogenase (quinone) activity / synaptic transmission, cholinergic / Regulation of ornithine decarboxylase (ODC) / NFE2L2 regulating anti-oxidant/detoxification enzymes / negative regulation of ferroptosis / nitric oxide biosynthetic process / xenobiotic metabolic process / removal of superoxide radicals / cell redox homeostasis / protein catabolic process / negative regulation of protein catabolic process / response to toxic substance / protein polyubiquitination / cellular response to oxidative stress / response to lipopolysaccharide / response to oxidative stress / innate immune response / synapse / RNA binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Flavodoxin-like fold / Flavodoxin-like fold / Flavoprotein-like superfamily
Similarity search - Domain/homology
Chem-EHL / FLAVIN-ADENINE DINUCLEOTIDE / NAD(P)H dehydrogenase [quinone] 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.501 Å
AuthorsYe, K. / Li, H.
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 23, 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_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: NAD(P)H dehydrogenase [quinone] 1
B: NAD(P)H dehydrogenase [quinone] 1
C: NAD(P)H dehydrogenase [quinone] 1
D: NAD(P)H dehydrogenase [quinone] 1
E: NAD(P)H dehydrogenase [quinone] 1
F: NAD(P)H dehydrogenase [quinone] 1
G: NAD(P)H dehydrogenase [quinone] 1
H: NAD(P)H dehydrogenase [quinone] 1
I: NAD(P)H dehydrogenase [quinone] 1
J: NAD(P)H dehydrogenase [quinone] 1
K: NAD(P)H dehydrogenase [quinone] 1
L: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)381,77036
Polymers369,31712
Non-polymers12,45324
Water4,486249
1
A: NAD(P)H dehydrogenase [quinone] 1
D: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9778
Polymers61,5532
Non-polymers2,4246
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9000 Å2
ΔGint-66 kcal/mol
Surface area21660 Å2
MethodPISA
2
B: NAD(P)H dehydrogenase [quinone] 1
F: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,5506
Polymers61,5532
Non-polymers1,9974
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8390 Å2
ΔGint-52 kcal/mol
Surface area21440 Å2
MethodPISA
3
C: NAD(P)H dehydrogenase [quinone] 1
hetero molecules

E: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,4545
Polymers61,5532
Non-polymers1,9013
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_654y+1,-x,z-1/41
Buried area8510 Å2
ΔGint-52 kcal/mol
Surface area21330 Å2
MethodPISA
4
G: NAD(P)H dehydrogenase [quinone] 1
H: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,4545
Polymers61,5532
Non-polymers1,9013
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8450 Å2
ΔGint-51 kcal/mol
Surface area21320 Å2
MethodPISA
5
I: NAD(P)H dehydrogenase [quinone] 1
J: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,8817
Polymers61,5532
Non-polymers2,3285
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9030 Å2
ΔGint-63 kcal/mol
Surface area21350 Å2
MethodPISA
6
K: NAD(P)H dehydrogenase [quinone] 1
L: NAD(P)H dehydrogenase [quinone] 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,4545
Polymers61,5532
Non-polymers1,9013
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8480 Å2
ΔGint-51 kcal/mol
Surface area21360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)147.882, 147.882, 209.791
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number76
Space group name H-MP41

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Components

#1: Protein
NAD(P)H dehydrogenase [quinone] 1 / Azoreductase / DT-diaphorase / DTD / Menadione reductase / NAD(P)H:quinone oxidoreductase 1 / ...Azoreductase / DT-diaphorase / DTD / Menadione reductase / NAD(P)H:quinone oxidoreductase 1 / Phylloquinone reductase / Quinone reductase 1 / QR1


Mass: 30776.412 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NQO1, DIA4, NMOR1 / Production host: Escherichia coli (E. coli)
References: UniProt: P15559, NAD(P)H dehydrogenase (quinone)
#2: Chemical
ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical
ChemComp-EHL / 5-methyl-N-(5-nitro-1,3-thiazol-2-yl)-3-phenyl-1,2-oxazole-4-carboxamide


Mass: 330.319 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C14H10N4O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 3.11 Å3/Da / Density % sol: 60.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.2M Lithium Sulfate,1.8M Ammonium Sulfate,0.1M Imidazole

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K-W / Detector: PIXEL / Date: May 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→32.66 Å / Num. obs: 154628 / % possible obs: 99.8 % / Redundancy: 6.8 % / CC1/2: 0.991 / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.046 / Rrim(I) all: 0.12 / Rsym value: 0.096 / Net I/σ(I): 13.89
Reflection shellResolution: 2.5→2.54 Å / Rmerge(I) obs: 0.635 / Num. unique obs: 7739 / CC1/2: 0.776 / Rpim(I) all: 0.281 / Rrim(I) all: 0.776 / Rsym value: 0.605

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Processing

Software
NameVersionClassification
HKL-2000data reduction
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2f1o

2f1o


Resolution: 2.501→29.576 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 28.22
RfactorNum. reflection% reflection
Rfree0.2645 2005 1.3 %
Rwork0.2222 --
obs0.2228 154572 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 113.01 Å2 / Biso mean: 45.8668 Å2 / Biso min: 15.64 Å2
Refinement stepCycle: final / Resolution: 2.501→29.576 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms25898 0 20 249 26167
Biso mean--75.59 36.78 -
Num. residues----3250
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.5011-2.56360.36371420.30381078299
2.5636-2.63290.30821420.281810863100
2.6329-2.71030.3431450.265210900100
2.7103-2.79770.33151410.259410901100
2.7977-2.89760.32671440.25710884100
2.8976-3.01350.32531420.260410916100
3.0135-3.15050.30531430.262910881100
3.1505-3.31640.30771440.253710877100
3.3164-3.52390.28691420.240110940100
3.5239-3.79550.26191450.21510907100
3.7955-4.17650.24911380.201110903100
4.1765-4.77860.21391450.167510958100
4.7786-6.01220.22731450.19410922100
6.0122-29.5760.19771470.20091093399

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