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- PDB-8pf4: Crystal structure of Trypanosoma brucei trypanothione reductase i... -

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Basic information

Entry
Database: PDB / ID: 8pf4
TitleCrystal structure of Trypanosoma brucei trypanothione reductase in complex with 4-(((5-((4-fluorophenethyl)carbamoyl)furan-2-yl)methyl)(4-fluorophenyl)carbamoyl)-1-methyl-1-(3-phenylpropyl)piperazin-1-ium
ComponentsTrypanothione reductase
KeywordsOXIDOREDUCTASE / oxidoreductase activity / nucleotide binding / flavoenzyme / inhibitor binding
Function / homology
Function and homology information


trypanothione-disulfide reductase / trypanothione-disulfide reductase (NADPH) activity / glutathione-disulfide reductase (NADPH) activity / glutathione metabolic process / cell redox homeostasis / flavin adenine dinucleotide binding / cellular response to oxidative stress / mitochondrion / cytosol
Similarity search - Function
Trypanothione reductase / : / Pyridine nucleotide-disulphide oxidoreductase, class I / Pyridine nucleotide-disulphide oxidoreductase, class I, active site / Pyridine nucleotide-disulphide oxidoreductases class-I active site. / Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain / Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain / FAD/NAD-linked reductase, dimerisation domain superfamily / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / FAD/NAD(P)-binding domain superfamily
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / IMIDAZOLE / DI(HYDROXYETHYL)ETHER / : / Trypanothione reductase
Similarity search - Component
Biological speciesTrypanosoma brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsExertier, C. / Ilari, A. / Fiorillo, A. / Antonelli, L.
Funding support Italy, 1items
OrganizationGrant numberCountry
Ministero dell Universita e della RicercaFISR2019_03796 Italy
CitationJournal: J.Med.Chem. / Year: 2024
Title: Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.
Authors: Exertier, C. / Salerno, A. / Antonelli, L. / Fiorillo, A. / Ocello, R. / Seghetti, F. / Caciolla, J. / Uliassi, E. / Masetti, M. / Fiorentino, E. / Orsini, S. / Di Muccio, T. / Ilari, A. / Bolognesi, M.L.
History
DepositionJun 15, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 3, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Trypanothione reductase
B: Trypanothione reductase
C: Trypanothione reductase
D: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)223,52053
Polymers213,9924
Non-polymers9,52849
Water21,3301184
1
A: Trypanothione reductase
B: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,85428
Polymers106,9962
Non-polymers4,85826
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14670 Å2
ΔGint-35 kcal/mol
Surface area37030 Å2
2
C: Trypanothione reductase
D: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,66625
Polymers106,9962
Non-polymers4,67023
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14470 Å2
ΔGint-36 kcal/mol
Surface area37190 Å2
Unit cell
Length a, b, c (Å)100.922, 63.635, 169.104
Angle α, β, γ (deg.)90.00, 97.29, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Trypanothione reductase / N(1) / N(8)-bis(glutathionyl)spermidine reductase


Mass: 53497.969 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: Owing to the flexibility of terminal segments, the electronic density is poorly defined which prevent us from being able to reconstruct the first G and the last four DSNL residues.
Source: (gene. exp.) Trypanosoma brucei (eukaryote) / Gene: DPX39_100110900 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A0A3L6KZJ1, trypanothione-disulfide reductase

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Non-polymers , 6 types, 1233 molecules

#2: Chemical
ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical
ChemComp-YIA / ~{N}-(4-fluorophenyl)-~{N}-[[5-[2-(4-fluorophenyl)ethylcarbamoyl]furan-2-yl]methyl]-4-methyl-4-(3-phenylpropyl)-1,4$l^{4}-diazinane-1-carboxamide


Mass: 601.706 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C35H39F2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical...
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 29 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical
ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H5N2
#6: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1184 / 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: 2.52 Å3/Da / Density % sol: 51.13 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 13-15% PEG3350, 22-24% MPD, 40 mM imidazole pH 7.5, 50 mM NaBr

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.8856 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 5, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8856 Å / Relative weight: 1
ReflectionResolution: 1.84→167.74 Å / Num. obs: 135585 / % possible obs: 94.7 % / Redundancy: 5.5 % / CC1/2: 0.994 / Net I/σ(I): 8.1
Reflection shellResolution: 1.84→2.03 Å / Mean I/σ(I) obs: 1.6 / Num. unique obs: 6779 / CC1/2: 0.655

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
autoPROCdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.84→167.74 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.918 / SU B: 4.276 / SU ML: 0.12 / Cross valid method: THROUGHOUT / ESU R: 0.197 / ESU R Free: 0.171 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22684 6796 5 %RANDOM
Rwork0.17868 ---
obs0.18113 128789 73.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.457 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0 Å20.08 Å2
2---0.07 Å2-0 Å2
3---0.05 Å2
Refinement stepCycle: 1 / Resolution: 1.84→167.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14826 0 643 1184 16653
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01316262
X-RAY DIFFRACTIONr_bond_other_d0.0010.01515694
X-RAY DIFFRACTIONr_angle_refined_deg1.4841.64322089
X-RAY DIFFRACTIONr_angle_other_deg1.2641.57636275
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.09352089
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.09922.493730
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.959152693
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4421581
X-RAY DIFFRACTIONr_chiral_restr0.0710.22111
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0218272
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023554
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_it1.5682.1387952
X-RAY DIFFRACTIONr_mcbond_other1.5682.1377951
X-RAY DIFFRACTIONr_mcangle_it2.5023.2019968
X-RAY DIFFRACTIONr_mcangle_other2.5023.2019969
X-RAY DIFFRACTIONr_scbond_it2.0692.5238310
X-RAY DIFFRACTIONr_scbond_other2.0692.5248311
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2983.62512052
X-RAY DIFFRACTIONr_long_range_B_refined5.37525.70818391
X-RAY DIFFRACTIONr_long_range_B_other5.37425.71418392
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.845→1.893 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 33 -
Rwork0.281 679 -
obs--5.27 %

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