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- PDB-8pf5: Crystal structure of Trypanosoma brucei trypanothione reductase i... -

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Basic information

Entry
Database: PDB / ID: 8pf5
TitleCrystal structure of Trypanosoma brucei trypanothione reductase in complex with 1-(3,4-dichlorobenzyl)-4-(((5-((4-fluorophenethyl)carbamoyl)furan-2-yl)methyl)carbamoyl)-1-(3-phenylpropyl)piperazin-1-ium
Components(Trypanothione ...) x 3
KeywordsOXIDOREDUCTASE / oxidoreductase activity / nucleotide binding / flavoenzyme / inhibitor binding
Function / homology
Function and homology information


trypanothione-disulfide reductase / trypanothione-disulfide reductase (NADPH) activity / cell redox homeostasis / flavin adenine dinucleotide binding / cytoplasm
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 / DI(HYDROXYETHYL)ETHER / : / Trypanothione reductase
Similarity search - Component
Biological speciesTrypanosoma brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsExertier, C. / Antonelli, L. / Fiorillo, A. / Ilari, A.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Ministry of EducationFISR2019_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)220,26918
Polymers213,9364
Non-polymers6,33314
Water6,125340
1
A: Trypanothione reductase
B: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,1649
Polymers106,9972
Non-polymers3,1677
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11410 Å2
ΔGint-69 kcal/mol
Surface area36630 Å2
2
C: Trypanothione reductase
D: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,1069
Polymers106,9392
Non-polymers3,1677
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11430 Å2
ΔGint-69 kcal/mol
Surface area37000 Å2
Unit cell
Length a, b, c (Å)100.960, 63.311, 169.112
Angle α, β, γ (deg.)90.00, 98.40, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Trypanothione ... , 3 types, 4 molecules ABCD

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


Mass: 53556.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Due to flexibility of the N- and C-terminal parts, the electronic density was not well defined which prevent us from reconstructing the polypeptid chain.
Source: (gene. exp.) Trypanosoma brucei (eukaryote) / Gene: DPX39_100110900 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A0A3L6KZJ1, trypanothione-disulfide reductase
#2: Protein Trypanothione reductase / N(1) / N(8)-bis(glutathionyl)spermidine reductase


Mass: 53440.914 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Due to flexibility of the N- and C-terminal parts, the electronic density was not well defined which prevent us from reconstructing the polypeptid chain.
Source: (gene. exp.) Trypanosoma brucei (eukaryote) / Gene: DPX39_100110900 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: A0A3L6KZJ1, trypanothione-disulfide reductase
#3: Protein Trypanothione reductase / N(1) / N(8)-bis(glutathionyl)spermidine reductase


Mass: 53497.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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 , 5 types, 354 molecules

#4: Chemical
ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide


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


Mass: 652.606 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C35H38Cl2FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#7: 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
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 2.5 Å3/Da / Density % sol: 50.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
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: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.42→167.3 Å / Num. obs: 81239 / % possible obs: 99.8 % / Redundancy: 5.8 % / CC1/2: 0.997 / Net I/σ(I): 11.56
Reflection shellResolution: 2.42→2.57 Å / Mean I/σ(I) obs: 2.08 / Num. unique obs: 12995 / CC1/2: 0.764

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
MOLREP11.7.03phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.42→55.83 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.911 / SU B: 10.48 / SU ML: 0.235 / Cross valid method: THROUGHOUT / ESU R: 0.49 / ESU R Free: 0.286 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25741 4052 5 %RANDOM
Rwork0.18988 ---
obs0.19329 77174 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.974 Å2
Baniso -1Baniso -2Baniso -3
1-2.07 Å20 Å20.87 Å2
2---1.53 Å20 Å2
3----0.77 Å2
Refinement stepCycle: 1 / Resolution: 2.42→55.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14847 0 436 340 15623
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01315734
X-RAY DIFFRACTIONr_bond_other_d0.0030.01514931
X-RAY DIFFRACTIONr_angle_refined_deg1.571.64121383
X-RAY DIFFRACTIONr_angle_other_deg1.2381.57734459
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.70651970
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.01722.671700
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.713152559
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5081571
X-RAY DIFFRACTIONr_chiral_restr0.0710.22049
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217730
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023425
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_it3.1174.1167844
X-RAY DIFFRACTIONr_mcbond_other3.1154.1157843
X-RAY DIFFRACTIONr_mcangle_it4.6276.1659802
X-RAY DIFFRACTIONr_mcangle_other4.6276.1659803
X-RAY DIFFRACTIONr_scbond_it3.464.5737890
X-RAY DIFFRACTIONr_scbond_other3.464.5737891
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.3566.67311574
X-RAY DIFFRACTIONr_long_range_B_refined7.26847.3516838
X-RAY DIFFRACTIONr_long_range_B_other7.26847.35116827
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.42→2.482 Å
RfactorNum. reflection% reflection
Rfree0.315 286 -
Rwork0.265 5599 -
obs--98.99 %

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