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- PDB-7o4d: QR2 inhibitor from a novel sulfanamide series to tackle age relat... -

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Basic information

Entry
Database: PDB / ID: 7o4d
TitleQR2 inhibitor from a novel sulfanamide series to tackle age related oxidative stress and cognitive decline
ComponentsRibosyldihydronicotinamide dehydrogenase [quinone]
KeywordsOXIDOREDUCTASE / Inhibitors
Function / homology
Function and homology information


ribosyldihydronicotinamide dehydrogenase (quinone) / dihydronicotinamide riboside quinone reductase activity / quinone catabolic process / resveratrol binding / oxidoreductase activity, acting on other nitrogenous compounds as donors / melatonin binding / NAD(P)H dehydrogenase (quinone) activity / Phase I - Functionalization of compounds / chloride ion binding / FAD binding ...ribosyldihydronicotinamide dehydrogenase (quinone) / dihydronicotinamide riboside quinone reductase activity / quinone catabolic process / resveratrol binding / oxidoreductase activity, acting on other nitrogenous compounds as donors / melatonin binding / NAD(P)H dehydrogenase (quinone) activity / Phase I - Functionalization of compounds / chloride ion binding / FAD binding / electron transfer activity / oxidoreductase activity / protein homodimerization activity / extracellular exosome / zinc ion binding / nucleoplasm / cytosol
Similarity search - Function
: / Flavodoxin-like fold / Flavodoxin-like fold / Flavoprotein-like superfamily
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / Chem-V1Z / Ribosyldihydronicotinamide dehydrogenase [quinone]
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.249 Å
AuthorsGould, N.L. / Scherer, G.R. / Carvalh, S. / Shurrush, K. / Edry, E. / Elkobi, A. / David, O. / Dym, O. / Albeck, S. / Peleg, Y. ...Gould, N.L. / Scherer, G.R. / Carvalh, S. / Shurrush, K. / Edry, E. / Elkobi, A. / David, O. / Dym, O. / Albeck, S. / Peleg, Y. / Germain, N. / Babaev, I. / Sharir, H. / Lefker, B. / Subramanyam, C. / Barr, H. / Rosenblum, K.
Funding support Israel, 1items
OrganizationGrant numberCountry
Israel Science Foundation258/20 Israel
CitationJournal: J.Clin.Invest. / Year: 2023
Title: Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.
Authors: Gould, N.L. / Scherer, G.R. / Carvalho, S. / Shurrush, K. / Kayyal, H. / Edry, E. / Elkobi, A. / David, O. / Foqara, M. / Thakar, D. / Pavesi, T. / Sharma, V. / Walker, M. / Maitland, M. / ...Authors: Gould, N.L. / Scherer, G.R. / Carvalho, S. / Shurrush, K. / Kayyal, H. / Edry, E. / Elkobi, A. / David, O. / Foqara, M. / Thakar, D. / Pavesi, T. / Sharma, V. / Walker, M. / Maitland, M. / Dym, O. / Albeck, S. / Peleg, Y. / Germain, N. / Babaev, I. / Sharir, H. / Lalzar, M. / Shklyar, B. / Hazut, N. / Khamaisy, M. / Levesque, M. / Lajoie, G. / Avoli, M. / Amitai, G. / Lefker, B. / Subramanyam, C. / Shilton, B. / Barr, H. / Rosenblum, K.
History
DepositionApr 6, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Feb 28, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ribosyldihydronicotinamide dehydrogenase [quinone]
B: Ribosyldihydronicotinamide dehydrogenase [quinone]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,5309
Polymers55,9922
Non-polymers2,5397
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7370 Å2
ΔGint-44 kcal/mol
Surface area17470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.031, 83.362, 106.486
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Ribosyldihydronicotinamide dehydrogenase [quinone] / NRH dehydrogenase [quinone] 2 / NRH:quinone oxidoreductase 2 / Quinone reductase 2 / QR2


Mass: 27995.787 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NQO2, NMOR2 / Production host: Escherichia coli (E. coli)
References: UniProt: P16083, ribosyldihydronicotinamide dehydrogenase (quinone)

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Non-polymers , 5 types, 123 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-V1Z / 8-methyl-2-(4-methyl-3-piperazin-1-ylsulfonyl-phenyl)imidazo[1,2-a]pyridine


Mass: 370.469 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H22N4O2S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.26 Å3/Da / Density % sol: 45.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.7 M ammonium tartrate diabasic and 50 mM Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5419 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5419 Å / Relative weight: 1
ReflectionResolution: 2.249→47.07 Å / Num. obs: 24796 / % possible obs: 99.9 % / Redundancy: 10.2 % / CC1/2: 0.993 / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.06999 / Rrim(I) all: 0.2292 / Net I/σ(I): 8.82
Reflection shellResolution: 2.249→2.329 Å / Redundancy: 10.2 % / Rmerge(I) obs: 0.6941 / Mean I/σ(I) obs: 3.51 / Num. unique obs: 2419 / CC1/2: 0.902 / Rpim(I) all: 0.2235 / Rrim(I) all: 0.7304

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LBU

5lbu


Resolution: 2.249→47.07 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2264 1231 4.97 %
Rwork0.1736 23549 -
obs0.1762 24780 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 91.54 Å2 / Biso mean: 19.0539 Å2 / Biso min: 4.75 Å2
Refinement stepCycle: final / Resolution: 2.249→47.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3577 0 165 116 3858
Biso mean--19.26 17.44 -
Num. residues----458
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.249-2.33850.23061390.1824252299
2.3385-2.4450.27521340.18672584100
2.445-2.57390.2731330.20122586100
2.5739-2.73510.29261330.20522592100
2.7351-2.94620.28211270.20952618100
2.9462-3.24270.28751370.20092582100
3.2427-3.71170.211290.17432630100
3.7117-4.67570.16781410.13282666100
4.6757-47.070.16961580.14452769100

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