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

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Basic information

Entry
Database: PDB / ID: 6btl
TitleCrystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD117 1-[2-(Piperazin-1-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole
ComponentsTrypanothione reductase
KeywordsOXIDOREDUCTASE/Inhibitor / Inhibitor / Complex / Sleeping Sickness / 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 / Pyridine nucleotide-disulphide oxidoreductase, class I, active site / Pyridine nucleotide-disulphide oxidoreductases class-I active site. / FAD/NAD-linked reductase, C-terminal dimerisation domain / 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 / Pyridine nucleotide-disulphide oxidoreductase, class I, active site / Pyridine nucleotide-disulphide oxidoreductases class-I active site. / FAD/NAD-linked reductase, C-terminal dimerisation domain / 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-RD7 / Trypanothione reductase
Similarity search - Component
Biological speciesTrypanosoma brucei brucei TREU927 (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.797 Å
AuthorsBryson, S. / De Gasparo, R. / Krauth-Siegel, R.L. / Diederich, F. / Pai, E.F.
Funding support Canada, Switzerland, Germany, United States, 6items
OrganizationGrant numberCountry
Natural Sciences and Engineering Research Council (NSERC, Canada)RGPIN-2015-04877 Canada
Canada Research Chairs Canada
ETH Reseach CouncilETH-01 13-2 Switzerland
German Research Foundation (DFG)KR 1242/8-1 Germany
Department of Energy (DOE, United States)DE-AC02-06CH11357 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)ACB-12002 United States
Citation
Journal: ChemMedChem / Year: 2018
Title: Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.
Authors: De Gasparo, R. / Brodbeck-Persch, E. / Bryson, S. / Hentzen, N.B. / Kaiser, M. / Pai, E.F. / Krauth-Siegel, R.L. / Diederich, F.
#1: Journal: ChemMedChem / Year: 2014
Title: Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase.
Authors: Persch, E. / Bryson, S. / Todoroff, N.K. / Eberle, C. / Thelemann, J. / Dirdjaja, N. / Kaiser, M. / Weber, M. / Derbani, H. / Brun, R. / Schneider, G. / Pai, E.F. / Krauth-Siegel, R.L. / Diederich, F.
History
DepositionDec 6, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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 1.4Oct 23, 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
A: Trypanothione reductase
B: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,82017
Polymers106,9962
Non-polymers3,82415
Water1629
1
A: Trypanothione reductase
B: Trypanothione reductase
hetero molecules

A: Trypanothione reductase
B: Trypanothione reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,63934
Polymers213,9924
Non-polymers7,64830
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_645y+1,x-1,-z1
Buried area24230 Å2
ΔGint-256 kcal/mol
Surface area77550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.664, 117.664, 225.163
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 AB

#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 TREU927 (eukaryote)
Strain: 927/4 GUTat10.1 / Gene: Tb10.406.0520 / Production host: Escherichia coli (E. coli)
References: UniProt: Q389T8, trypanothione-disulfide reductase

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Non-polymers , 6 types, 24 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-RD7 / 1-[2-(piperazin-1-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole


Mass: 463.681 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H37N5S
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: 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
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 3.66 Å3/Da / Density % sol: 66.4 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Adding 5 microL of 10 mM inhibitor in DMSO to 95 microL of protein solution (10mg/ml; 20 mM TRIS, pH8.0), then mixing 2 microL of protein solution with 2 microL of well solution (0.1 M ...Details: Adding 5 microL of 10 mM inhibitor in DMSO to 95 microL of protein solution (10mg/ml; 20 mM TRIS, pH8.0), then mixing 2 microL of protein solution with 2 microL of well solution (0.1 M HEPES, pH 7.5, 2.0 M (NH4)2SO4).

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 3, 2016 / Details: collimator
RadiationMonochromator: double crystal monochromator and K-B pair of bimorph mirrors for vertical and horizontal focusing
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.797→47.7 Å / Num. obs: 39719 / % possible obs: 99.4 % / Redundancy: 8.6 % / Biso Wilson estimate: 79.3 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.137 / Rpim(I) all: 0.049 / Rrim(I) all: 0.146 / Net I/σ(I): 16.8
Reflection shellResolution: 2.797→2.9 Å / Redundancy: 7.2 % / Rmerge(I) obs: 1.609 / Num. unique obs: 3684 / CC1/2: 0.423 / Rpim(I) all: 0.618 / Rrim(I) all: 1.728 / % possible all: 95

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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: 2WOI

2woi


Resolution: 2.797→47.671 Å / SU ML: 0.4 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2363 1917 4.84 %Random selection
Rwork0.1965 ---
obs0.1985 39619 99.43 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.797→47.671 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7472 0 251 9 7732
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047896
X-RAY DIFFRACTIONf_angle_d0.98510730
X-RAY DIFFRACTIONf_dihedral_angle_d13.6654693
X-RAY DIFFRACTIONf_chiral_restr0.0431194
X-RAY DIFFRACTIONf_plane_restr0.0031345
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7973-2.86730.37131240.36962489X-RAY DIFFRACTION94
2.8673-2.94480.3711250.34132634X-RAY DIFFRACTION99
2.9448-3.03140.40141240.33182659X-RAY DIFFRACTION100
3.0314-3.12920.31911280.28442672X-RAY DIFFRACTION100
3.1292-3.24110.32781590.26882648X-RAY DIFFRACTION100
3.2411-3.37080.25191380.24162674X-RAY DIFFRACTION100
3.3708-3.52420.2381290.21742678X-RAY DIFFRACTION100
3.5242-3.70990.26251290.19992694X-RAY DIFFRACTION100
3.7099-3.94220.22741470.19252688X-RAY DIFFRACTION100
3.9422-4.24640.24511450.17572690X-RAY DIFFRACTION100
4.2464-4.67340.21121340.15292722X-RAY DIFFRACTION100
4.6734-5.34890.1931310.15772757X-RAY DIFFRACTION100
5.3489-6.7360.23581420.19982769X-RAY DIFFRACTION100
6.736-47.67760.19661620.16492928X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 31.965 Å / Origin y: -13.1127 Å / Origin z: 6.9945 Å
111213212223313233
T0.4866 Å20.0996 Å20.0338 Å2-0.543 Å20.0498 Å2--0.5294 Å2
L0.8221 °2-0.3939 °2-0.3245 °2-1.6489 °20.6463 °2--0.9868 °2
S-0.067 Å °-0.2296 Å °-0.1213 Å °0.1783 Å °0.0352 Å °-0.3338 Å °0.3682 Å °0.2277 Å °0.0289 Å °
Refinement TLS groupSelection details: all

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