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

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Basic information

Entry
Database: PDB / ID: 6oex
TitleCrystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor 3-(2-{1-[2-(Piperidin-4-yl)ethyl]-1H-indol-5-yl}-5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3- thiazol-4-yl)-N-(2,2,2-trifluoroethyl)prop-2-yn-1-amine
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 / glutathione-disulfide reductase (NADPH) activity / glycosome / thioredoxin-disulfide reductase (NADPH) activity / ciliary plasm / glutathione metabolic process / cell redox homeostasis / cellular response to oxidative stress / flavin adenine dinucleotide binding ...trypanothione-disulfide reductase / trypanothione-disulfide reductase (NADPH) activity / glutathione-disulfide reductase (NADPH) activity / glycosome / thioredoxin-disulfide reductase (NADPH) activity / ciliary plasm / glutathione metabolic process / cell redox homeostasis / cellular response to oxidative stress / flavin adenine dinucleotide binding / mitochondrion / nucleoplasm / metal ion binding / cytosol / 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-M9Y / 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

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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)110,43110
Polymers106,9962
Non-polymers3,4358
Water10,142563
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10900 Å2
ΔGint-85 kcal/mol
Surface area36670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.190, 117.190, 224.170
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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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)
References: UniProt: Q389T8, trypanothione-disulfide reductase

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Non-polymers , 5 types, 571 molecules

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


Mass: 785.550 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / 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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-M9Y / 3-(2-{1-[2-(piperidin-4-yl)ethyl]-1H-indol-5-yl}-5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-4-yl)-N-(2,2,2-trifluoroethyl)prop-2-yn-1-amine


Mass: 597.780 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H42F3N5S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 563 / Source method: isolated from a natural source / Formula: H2O

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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: 3.6 Å3/Da / Density % sol: 65.8 % / 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 2 weeks.

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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→46.4 Å / Num. obs: 90546 / % possible obs: 96 % / Redundancy: 13.2 % / CC1/2: 0.999 / Net I/σ(I): 16.9
Reflection shellResolution: 2.1→2.18 Å / Num. unique obs: 7051 / CC1/2: 0.637

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NEV

4nev


Resolution: 2.1→46.4 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.19
RfactorNum. reflection% reflectionSelection details
Rfree0.192 4393 4.97 %random selection
Rwork0.1757 ---
obs0.1765 88365 96.48 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→46.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7383 0 230 563 8176
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037821
X-RAY DIFFRACTIONf_angle_d0.62210644
X-RAY DIFFRACTIONf_dihedral_angle_d15.3894678
X-RAY DIFFRACTIONf_chiral_restr0.0451189
X-RAY DIFFRACTIONf_plane_restr0.0031385
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.12390.3065970.25641960X-RAY DIFFRACTION69
2.1239-2.14890.25341100.26132251X-RAY DIFFRACTION79
2.1489-2.17510.26931170.24482516X-RAY DIFFRACTION87
2.1751-2.20260.26231460.22182696X-RAY DIFFRACTION95
2.2026-2.23160.24251430.21962806X-RAY DIFFRACTION99
2.2316-2.26220.22311080.23091891X-RAY DIFFRACTION66
2.2622-2.29450.24731780.21812848X-RAY DIFFRACTION100
2.2945-2.32870.23071530.21252853X-RAY DIFFRACTION100
2.3287-2.36510.23281490.20272869X-RAY DIFFRACTION100
2.3651-2.40390.26321460.19222891X-RAY DIFFRACTION100
2.4039-2.44530.25581580.19882845X-RAY DIFFRACTION100
2.4453-2.48980.24261380.18522881X-RAY DIFFRACTION100
2.4898-2.53770.23221400.19052859X-RAY DIFFRACTION100
2.5377-2.58950.20051360.18582893X-RAY DIFFRACTION100
2.5895-2.64580.21951410.17532889X-RAY DIFFRACTION100
2.6458-2.70730.20421770.17912866X-RAY DIFFRACTION100
2.7073-2.7750.18511620.17072862X-RAY DIFFRACTION100
2.775-2.85010.22511430.17392910X-RAY DIFFRACTION100
2.8501-2.93390.19441560.18272871X-RAY DIFFRACTION100
2.9339-3.02860.1951620.1782882X-RAY DIFFRACTION100
3.0286-3.13690.21691530.16512883X-RAY DIFFRACTION100
3.1369-3.26250.1961530.17062900X-RAY DIFFRACTION100
3.2625-3.41090.17651430.16712936X-RAY DIFFRACTION100
3.4109-3.59070.16931360.14872926X-RAY DIFFRACTION100
3.5907-3.81560.16191530.15282928X-RAY DIFFRACTION100
3.8156-4.11020.16121190.14322963X-RAY DIFFRACTION100
4.1102-4.52360.15011780.14192955X-RAY DIFFRACTION100
4.5236-5.17780.15881650.1512955X-RAY DIFFRACTION100
5.1778-6.52190.19911690.21323015X-RAY DIFFRACTION100
6.5219-56.06240.20131640.20543172X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -12.4489 Å / Origin y: -31.9354 Å / Origin z: -49.5888 Å
111213212223313233
T0.3262 Å2-0.0521 Å20.0265 Å2-0.2668 Å2-0.0108 Å2--0.2634 Å2
L0.8196 °20.2131 °20.4308 °2-0.3447 °20.2207 °2--0.5571 °2
S0.0684 Å °-0.1176 Å °-0.1241 Å °0.1159 Å °-0.0739 Å °0.0269 Å °0.1194 Å °-0.1702 Å °0.0092 Å °
Refinement TLS groupSelection details: all

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