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- PDB-6t98: Trypanothione Reductase from Leishmania infantum in complex with 9a -

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Basic information

Entry
Database: PDB / ID: 6t98
TitleTrypanothione Reductase from Leishmania infantum in complex with 9a
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 / 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 / Chem-MWZ / Trypanothione reductase
Similarity search - Component
Biological speciesLeishmania infantum (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsCarriles, A.A. / Hermoso, J.A.
Funding support Spain, 1items
OrganizationGrant numberCountry
Spanish Ministry of Economy and Competitiveness Spain
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity.
Authors: de Lucio, H. / Revuelto, A. / Carriles, A.A. / de Castro, S. / Garcia-Gonzalez, S. / Garcia-Soriano, J.C. / Alcon-Calderon, M. / Sanchez-Murcia, P.A. / Hermoso, J.A. / Gago, F. / Camarasa, M. ...Authors: de Lucio, H. / Revuelto, A. / Carriles, A.A. / de Castro, S. / Garcia-Gonzalez, S. / Garcia-Soriano, J.C. / Alcon-Calderon, M. / 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 1.2Apr 5, 2023Group: Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / database_2 / struct
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct.title
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)55,03912
Polymers52,8691
Non-polymers2,17011
Water2,342130
1
A: Trypanothione reductase
hetero molecules

A: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,07824
Polymers105,7382
Non-polymers4,34022
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area13470 Å2
ΔGint-216 kcal/mol
Surface area36590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.430, 103.430, 192.790
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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 , 6 types, 141 molecules

#2: Chemical ChemComp-MWZ / 4-[3-methyl-1-[4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]-3-(2-piperidin-4-ylethoxy)phenyl]-1,2,3-triazol-3-ium-4-yl]butan-1-amine


Mass: 545.762 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H41N6OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 4.88 Å3/Da / Density % sol: 74.78 %
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: 3→68.38 Å / Num. obs: 21445 / % possible obs: 98.9 % / Redundancy: 5.3 % / CC1/2: 0.965 / Rmerge(I) obs: 0.172 / Rpim(I) all: 0.081 / Rrim(I) all: 0.192 / Net I/σ(I): 5.6
Reflection shellResolution: 3→3.18 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.665 / Num. unique obs: 3411 / CC1/2: 0.831 / Rpim(I) all: 0.298 / Rrim(I) all: 0.733 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
Aimless0.7.3data scaling
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JK6

2jk6


Resolution: 3→68.38 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.875 / SU B: 37.121 / SU ML: 0.315 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.634 / ESU R Free: 0.35 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2571 1051 4.9 %RANDOM
Rwork0.2149 ---
obs0.217 20315 98.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 236.18 Å2 / Biso mean: 65.543 Å2 / Biso min: 25.46 Å2
Baniso -1Baniso -2Baniso -3
1-2.85 Å20 Å20 Å2
2--2.85 Å2-0 Å2
3----5.7 Å2
Refinement stepCycle: final / Resolution: 3→68.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3701 0 138 130 3969
Biso mean--90.12 51.23 -
Num. residues----489
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0133925
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173580
X-RAY DIFFRACTIONr_angle_refined_deg1.5111.6555326
X-RAY DIFFRACTIONr_angle_other_deg1.2511.598317
X-RAY DIFFRACTIONr_dihedral_angle_1_deg13.3135.308503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.27422.701174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.25115625
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4591519
X-RAY DIFFRACTIONr_chiral_restr0.0630.2510
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024718
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02785
LS refinement shellResolution: 3→3.078 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 73 -
Rwork0.331 1489 -
all-1562 -
obs--99.55 %
Refinement TLS params.Method: refined / Origin x: 1.076 Å / Origin y: 28.137 Å / Origin z: 0.939 Å
111213212223313233
T0.0686 Å2-0.0099 Å20.0175 Å2-0.1376 Å20.0288 Å2--0.1028 Å2
L1.1403 °2-0.4624 °20.7032 °2-1.1103 °2-0.7288 °2--2.0265 °2
S-0.0513 Å °-0.2037 Å °0.0341 Å °0.1792 Å °0.1416 Å °0.1317 Å °-0.1947 Å °-0.3875 Å °-0.0903 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 37
2X-RAY DIFFRACTION1A38 - 93
3X-RAY DIFFRACTION1A94 - 148
4X-RAY DIFFRACTION1A149 - 291
5X-RAY DIFFRACTION1A292 - 406
6X-RAY DIFFRACTION1A407 - 488

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