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- PDB-6oey: Crystal structure of Trypanothione Reductase from Trypanosoma bru... -

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Basic information

Entry
Database: PDB / ID: 6oey
TitleCrystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor (+)-5-{5-[1-(Pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1-{[(2S)-pyrrolidin-2-yl]methyl}-1H-indole
ComponentsTrypanothione reductase
Keywordsoxidoreductase/oxidoreductase inhibitor / Trypanosoma / trypanothione / inhibitor / sleeping sickness / OXIDOREDUCTASE / oxidoreductase-oxidoreductase inhibitor complex
Function / homology
Function and homology information


trypanothione-disulfide reductase / trypanothione-disulfide reductase (NADPH) activity / glycosome / ciliary plasm / thioredoxin-disulfide reductase (NADPH) activity / cell redox homeostasis / flavin adenine dinucleotide binding / nucleoplasm / metal ion binding / cytoplasm
Similarity search - Function
Trypanothione reductase / : / Pyridine nucleotide-disulphide oxidoreductase, class I / FAD/NAD-linked reductase, C-terminal dimerisation domain / 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 ...Trypanothione reductase / : / Pyridine nucleotide-disulphide oxidoreductase, class I / FAD/NAD-linked reductase, C-terminal dimerisation domain / 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 / Enolase-like; domain 1 / FAD/NAD(P)-binding domain / FAD/NAD(P)-binding domain / 3-Layer(bba) Sandwich / FAD/NAD(P)-binding domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / Chem-M9S / Trypanothione reductase
Similarity search - Component
Biological speciesTrypanosoma brucei brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsHalgas, O. / De Gasparo, R. / Harangozo, D. / Krauth-Siegel, R.L. / Diederich, F. / Pai, E.F.
Funding support Canada, 1items
OrganizationGrant numberCountry
Natural Sciences and Engineering Research Council (NSERC, Canada)RGPIN-2015-04877 Canada
CitationJournal: Chemistry / Year: 2019
Title: Targeting a Large Active Site: Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase.
Authors: De Gasparo, R. / Halgas, O. / Harangozo, D. / Kaiser, M. / Pai, E.F. / Krauth-Siegel, R.L. / Diederich, F.
History
DepositionMar 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 11, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 11, 2023Group: 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)111,07013
Polymers106,9962
Non-polymers4,07411
Water10,413578
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10910 Å2
ΔGint-94 kcal/mol
Surface area37180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.360, 117.360, 224.180
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11B-506-

M9S

21B-506-

M9S

31B-506-

M9S

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Components

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Protein , 1 types, 2 molecules BA

#1: Protein Trypanothione reductase


Mass: 53497.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei brucei (strain 927/4 GUTat10.1) (eukaryote)
Strain: 927/4 GUTat10.1 / Gene: Tb10.406.0520 / Plasmid: PET3ATBTRYR
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Strain (production host): BL21-Gold(DE3)pLysS AG
References: UniProt: Q389T8, trypanothione-disulfide reductase

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Non-polymers , 5 types, 589 molecules

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


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-M9S / 5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1-{[(2S)-pyrrolidin-2-yl]methyl}-1H-indole


Mass: 434.640 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H34N4S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 578 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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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: 3.47 Å3/Da / Density % sol: 64.5 % / Description: yellowish tetragonal bipyramid
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 2 microL of protein were mixed with 2 microL of well solution (500 microL; 0.1 M HEPES, pH 7.5, 2.2 M (NH4)2SO4); crystals grew within 2weeks

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→52 Å / Num. obs: 91815 / % possible obs: 99 % / Redundancy: 13.2 % / CC1/2: 0.999 / Net I/σ(I): 13.5
Reflection shellResolution: 2.1→2.18 Å / Num. unique obs: 8473 / CC1/2: 0.598

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NEV

4nev


Resolution: 2.1→52 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.13
RfactorNum. reflection% reflection
Rfree0.2066 4746 4.98 %
Rwork0.1761 --
obs0.1777 95235 96.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7383 0 275 578 8236
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0137880
X-RAY DIFFRACTIONf_angle_d1.12310731
X-RAY DIFFRACTIONf_dihedral_angle_d15.714703
X-RAY DIFFRACTIONf_chiral_restr0.0631192
X-RAY DIFFRACTIONf_plane_restr0.0081422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0462-2.06950.2709410.27171212X-RAY DIFFRACTION39
2.0695-2.09380.35751090.27672021X-RAY DIFFRACTION65
2.0938-2.11940.31741210.25612519X-RAY DIFFRACTION82
2.1194-2.14620.25741710.24912935X-RAY DIFFRACTION95
2.1462-2.17450.23851670.24353089X-RAY DIFFRACTION100
2.1745-2.20420.24031620.23353107X-RAY DIFFRACTION100
2.2042-2.23570.24331690.23013073X-RAY DIFFRACTION100
2.2357-2.26910.28531560.22153115X-RAY DIFFRACTION100
2.2691-2.30460.27931710.21673113X-RAY DIFFRACTION100
2.3046-2.34230.27641490.20723116X-RAY DIFFRACTION100
2.3423-2.38270.2331590.19993101X-RAY DIFFRACTION100
2.3827-2.42610.24451610.19343089X-RAY DIFFRACTION100
2.4261-2.47270.22931710.18493102X-RAY DIFFRACTION100
2.4727-2.52320.21541580.18173124X-RAY DIFFRACTION100
2.5232-2.57810.22371710.18243107X-RAY DIFFRACTION100
2.5781-2.6380.20741920.17483099X-RAY DIFFRACTION100
2.638-2.7040.21121600.17453122X-RAY DIFFRACTION100
2.704-2.77710.22071710.17693098X-RAY DIFFRACTION100
2.7771-2.85880.22681650.17583154X-RAY DIFFRACTION100
2.8588-2.95110.21871640.17633138X-RAY DIFFRACTION100
2.9511-3.05660.22491640.17393111X-RAY DIFFRACTION100
3.0566-3.17890.20791520.17463164X-RAY DIFFRACTION100
3.1789-3.32360.20941580.17553164X-RAY DIFFRACTION100
3.3236-3.49880.18641530.17033159X-RAY DIFFRACTION100
3.4988-3.7180.18871400.16363198X-RAY DIFFRACTION100
3.718-4.0050.17741570.14843187X-RAY DIFFRACTION100
4.005-4.40790.18221720.13673191X-RAY DIFFRACTION100
4.4079-5.04540.14891950.13713200X-RAY DIFFRACTION100
5.0454-6.35530.19461740.18713267X-RAY DIFFRACTION100
6.3553-56.78930.22091930.1993414X-RAY DIFFRACTION99

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