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- PDB-6t97: Trypanothione Reductase from Leismania infantum in complex with TRL190 -

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Basic information

Entry
Database: PDB / ID: 6t97
TitleTrypanothione Reductase from Leismania infantum in complex with TRL190
ComponentsTrypanothione reductase
KeywordsFLAVOPROTEIN / Inhibitor / Complex / Oxidoreductase / Leishmania / Drug
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 / cellular response to oxidative stress / flavin adenine dinucleotide binding / 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 / Chem-MWW / Trypanothione reductase
Similarity search - Component
Biological speciesLeishmania infantum (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsCarriles, A. / Hermoso, J.A.
Funding support Spain, 1items
OrganizationGrant numberCountry
Spanish Ministry of Economy and Competitiveness Spain
CitationJournal: To Be Published
Title: Scaffold hopping identifies new triazole-and triazolium-based inhibitors of Leishmania infantum Trypanothione Reductase with potent and selective antileishmanial activity
Authors: Revuelto, A. / de Lucio, H. / Carriles, A. / Garcia Soriano, J.C. / Sanchez-Murcia, P.A. / Hermoso, J.A. / Gago, F. / Camarasa, M.J. / Jimenez-Ruiz, A. / Velazquez, S.
History
DepositionOct 26, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 2, 2021Group: Refinement description / Category: pdbx_refine_tls / pdbx_refine_tls_group
Item: _pdbx_refine_tls.origin_x / _pdbx_refine_tls.origin_y ..._pdbx_refine_tls.origin_x / _pdbx_refine_tls.origin_y / _pdbx_refine_tls.origin_z / _pdbx_refine_tls_group.end_auth_seq_id
Revision 1.2Jan 24, 2024Group: 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
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: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,94611
Polymers52,8691
Non-polymers2,07710
Water4,071226
1
A: Trypanothione reductase
hetero molecules

A: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,89222
Polymers105,7382
Non-polymers4,15420
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_554-y,-x,-z-1/21
Buried area12350 Å2
ΔGint-211 kcal/mol
Surface area37250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.110, 103.110, 191.675
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-806-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Trypanothione reductase / Trypanothione_reductase


Mass: 52868.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Leishmania infantum (eukaryote) / Gene: TRYR, LINF_050008500, LINJ_05_0350 / Production host: Escherichia coli (E. coli)
References: UniProt: A4HSF7, trypanothione-disulfide reductase

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Non-polymers , 5 types, 236 molecules

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


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-MWW / 4-[1-[4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]-3-(2-piperidin-4-ylethoxy)phenyl]-1,2,3-triazol-4-yl]butan-1-amine


Mass: 530.727 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H38N6OS / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 226 / 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: 4.82 Å3/Da / Density % sol: 74.47 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 2.2M ammonium sulphate, 0.1M Tris-HCl pH 8-8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 24, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 2.8→48.1 Å / Num. obs: 26273 / % possible obs: 99.9 % / Redundancy: 7.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.035 / Rrim(I) all: 0.095 / Net I/σ(I): 10.9
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.736 / Num. unique obs: 3759 / CC1/2: 0.943 / Rpim(I) all: 0.286 / Rrim(I) all: 0.791 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
Aimless0.7.3data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JK6
Resolution: 2.8→48.1 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.916 / SU B: 23.812 / SU ML: 0.245 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.403 / ESU R Free: 0.298
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2576 1338 5.1 %RANDOM
Rwork0.2041 ---
obs0.2069 24863 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 153.02 Å2 / Biso mean: 65.685 Å2 / Biso min: 23.59 Å2
Baniso -1Baniso -2Baniso -3
1-2.87 Å20 Å2-0 Å2
2--2.87 Å20 Å2
3----5.74 Å2
Refinement stepCycle: final / Resolution: 2.8→48.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3701 0 133 226 4060
Biso mean--96.16 57.45 -
Num. residues----489
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0133913
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173568
X-RAY DIFFRACTIONr_angle_refined_deg1.441.6555307
X-RAY DIFFRACTIONr_angle_other_deg1.1811.598289
X-RAY DIFFRACTIONr_dihedral_angle_1_deg14.1525.31500
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.29322.659173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.42115623
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6261519
X-RAY DIFFRACTIONr_chiral_restr0.060.2509
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024699
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02783
LS refinement shellResolution: 2.8→2.873 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 89 -
Rwork0.366 1800 -
all-1889 -
obs--99.74 %
Refinement TLS params.Method: refined / Origin x: 27.997 Å / Origin y: -1.204 Å / Origin z: -46.891 Å
111213212223313233
T0.1412 Å20.0305 Å20.0127 Å2-0.0837 Å2-0.0284 Å2--0.023 Å2
L1.0091 °20.339 °2-0.6886 °2-0.9972 °2-0.6356 °2--2.0597 °2
S0.1321 Å °-0.1131 Å °0.1373 Å °0.1666 Å °-0.0157 Å °0.008 Å °-0.3621 Å °0.1623 Å °-0.1164 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 37
2X-RAY DIFFRACTION1A38 - 93
3X-RAY DIFFRACTION1A94 - 118
4X-RAY DIFFRACTION1A119 - 160
5X-RAY DIFFRACTION1A161 - 309
6X-RAY DIFFRACTION1A310 - 365
7X-RAY DIFFRACTION1A366 - 488

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