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

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Basic information

Entry
Database: PDB / ID: 6oez
TitleCrystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor (+)-N-(Cyclobutylmethyl)-3-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-2-(1-{[(2S)-pyrro-lidin-2-yl]methyl}-1H-indol-5-yl)-1,3-thiazol-4-yl}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 / glycosome / thioredoxin-disulfide reductase (NADPH) activity / ciliary plasm / 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-M9J / Trypanothione reductase
Similarity search - Component
Biological speciesTrypanosoma brucei brucei (eukaryote)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)110,1558
Polymers106,9962
Non-polymers3,1596
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10640 Å2
ΔGint-64 kcal/mol
Surface area36810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.526, 117.526, 224.522
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#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
#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-M9J / N-(cyclobutylmethyl)-3-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-2-(1-{[(2S)-pyrrolidin-2-yl]methyl}-1H-indol-5-yl)-1,3-thiazol-4-yl}prop-2-yn-1-amine


Mass: 555.820 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H45N5S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer detailsDue to the crystal packing density for chain B and its ligands is better than that for chain A in ...Due to the crystal packing density for chain B and its ligands is better than that for chain A in all the structures of this protein-inhibitor complexes that we have solved so far

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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: 3.62 Å3/Da / Density % sol: 66.05 % / 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); crystal grew within 2weeks

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.5418 Å
DetectorType: DECTRIS EIGER R 1M / Detector: PIXEL / Date: Oct 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→29.1 Å / Num. obs: 55114 / % possible obs: 99 % / Redundancy: 12.4 % / CC1/2: 0.993 / Net I/σ(I): 9.96
Reflection shellResolution: 2.5→2.59 Å / Num. unique obs: 5386 / Rpim(I) all: 0.745

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Processing

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

4nev


Resolution: 2.5→29.1 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 22.32
RfactorNum. reflection% reflection
Rfree0.235 2724 4.96 %
Rwork0.2171 --
obs0.218 54892 99.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.5→29.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7375 0 216 204 7795
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037771
X-RAY DIFFRACTIONf_angle_d0.64710571
X-RAY DIFFRACTIONf_dihedral_angle_d16.2494647
X-RAY DIFFRACTIONf_chiral_restr0.0481185
X-RAY DIFFRACTIONf_plane_restr0.0031375
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.54550.3361510.31392626X-RAY DIFFRACTION99
2.5455-2.59440.32391360.27552716X-RAY DIFFRACTION100
2.5944-2.64730.28931600.28412683X-RAY DIFFRACTION100
2.6473-2.70490.27361380.26292705X-RAY DIFFRACTION100
2.7049-2.76770.26921360.26062728X-RAY DIFFRACTION100
2.7677-2.83690.27931350.24842708X-RAY DIFFRACTION100
2.8369-2.91350.25481460.25572709X-RAY DIFFRACTION99
2.9135-2.99920.27021240.25442725X-RAY DIFFRACTION100
2.9992-3.09590.28991520.25072733X-RAY DIFFRACTION100
3.0959-3.20640.27431210.24392737X-RAY DIFFRACTION100
3.2064-3.33460.25241570.23472714X-RAY DIFFRACTION100
3.3346-3.48620.2431600.2212707X-RAY DIFFRACTION100
3.4862-3.66960.2321510.20312747X-RAY DIFFRACTION100
3.6696-3.89910.20951360.19352757X-RAY DIFFRACTION100
3.8991-4.19940.19531730.18022734X-RAY DIFFRACTION99
4.1994-4.62050.16871300.16812780X-RAY DIFFRACTION99
4.6205-5.28580.16671150.17162833X-RAY DIFFRACTION100
5.2858-6.6470.22951540.22052837X-RAY DIFFRACTION100
6.647-29.52230.22231490.1932989X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -12.6141 Å / Origin y: -32.0126 Å / Origin z: -49.5334 Å
111213212223313233
T0.3176 Å2-0.0342 Å20.0274 Å2-0.26 Å2-0.0054 Å2--0.2494 Å2
L1.0801 °20.3401 °20.5355 °2-0.3321 °20.2438 °2--0.5455 °2
S0.0597 Å °-0.1361 Å °-0.0868 Å °0.1078 Å °-0.0784 Å °0.0486 Å °0.0823 Å °-0.1575 Å °0.0181 Å °
Refinement TLS groupSelection details: all

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