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- PDB-6gxg: Tryparedoxin from Trypanosoma brucei in complex with CFT -

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Basic information

Entry
Database: PDB / ID: 6gxg
TitleTryparedoxin from Trypanosoma brucei in complex with CFT
Components(Tryparedoxin) x 2
KeywordsOXIDOREDUCTASE / Covalent Inhibitor / Photoreduction / Inhibitor-Induced Dimerization / Monomer-Dimer Mixture
Function / homology
Function and homology information


thioredoxin-disulfide reductase (NADPH) activity / negative regulation of Wnt signaling pathway / negative regulation of protein ubiquitination / nucleus
Similarity search - Function
TryX and NRX, thioredoxin domain / Thioredoxin-like / Thioredoxin-like fold / Thioredoxin, conserved site / Thioredoxin family active site. / Thioredoxin domain profile. / Thioredoxin domain / Glutaredoxin / Glutaredoxin / Thioredoxin-like superfamily ...TryX and NRX, thioredoxin domain / Thioredoxin-like / Thioredoxin-like fold / Thioredoxin, conserved site / Thioredoxin family active site. / Thioredoxin domain profile. / Thioredoxin domain / Glutaredoxin / Glutaredoxin / Thioredoxin-like superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-FFN / Tryparedoxin
Similarity search - Component
Biological speciesTrypanosoma brucei brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsBader, N. / Wagner, A. / Hellmich, U. / Schindelin, H.
CitationJournal: Angew Chem Int Ed Engl / Year: 2019
Title: Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes.
Authors: Annika Wagner / Thien Anh Le / Martha Brennich / Philipp Klein / Nicole Bader / Erika Diehl / Daniel Paszek / A Katharina Weickhmann / Natalie Dirdjaja / R Luise Krauth-Siegel / Bernd Engels ...Authors: Annika Wagner / Thien Anh Le / Martha Brennich / Philipp Klein / Nicole Bader / Erika Diehl / Daniel Paszek / A Katharina Weickhmann / Natalie Dirdjaja / R Luise Krauth-Siegel / Bernd Engels / Till Opatz / Hermann Schindelin / Ute A Hellmich /
Abstract: Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus ...Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, protein-protein, and inhibitor-protein interactions stabilize the dimer. The behavior of this efficient antitrypanosomal molecule thus constitutes an exquisite example of chemically induced dimerization with a small, monovalent ligand that can be exploited for future drug design.
History
DepositionJun 27, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 16, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tryparedoxin
B: Tryparedoxin
C: Tryparedoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,0248
Polymers48,0593
Non-polymers9655
Water7,530418
1
A: Tryparedoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1392
Polymers15,8791
Non-polymers2601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tryparedoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,4433
Polymers16,0901
Non-polymers3522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tryparedoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,4433
Polymers16,0901
Non-polymers3522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.680, 95.736, 48.043
Angle α, β, γ (deg.)90.00, 96.61, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tryparedoxin / TryX


Mass: 15878.901 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei brucei (eukaryote) / Production host: Escherichia coli (E. coli) / References: UniProt: O77404
#2: Protein Tryparedoxin / TryX


Mass: 16090.119 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei brucei (eukaryote) / Production host: Escherichia coli (E. coli) / References: UniProt: O77404
#3: Chemical ChemComp-FFN / 5-(4-fluorophenyl)-2-methyl-3~{H}-thieno[2,3-d]pyrimidin-4-one


Mass: 260.287 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C13H9FN2OS / Feature type: SUBJECT OF INVESTIGATION
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 418 / 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: 1.87 Å3/Da / Density % sol: 34.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 1.045 M Na-citrate; 100 mM Na-acetate buffer

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.07227 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07227 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 45750 / % possible obs: 97.4 % / Redundancy: 6.8 % / Biso Wilson estimate: 11.9 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.134 / Rpim(I) all: 0.056 / Rrim(I) all: 0.146 / Net I/σ(I): 9.6
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 7.1 % / Rmerge(I) obs: 1.441 / Num. unique obs: 2210 / CC1/2: 0.6 / Rpim(I) all: 0.577 / Rrim(I) all: 1.554 / % possible all: 95.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1o73

1o73


Resolution: 1.6→20 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.962 / SU B: 2.017 / SU ML: 0.067 / Cross valid method: THROUGHOUT / ESU R: 0.095 / ESU R Free: 0.089 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17701 2241 4.9 %RANDOM
Rwork0.15 ---
obs0.15133 43454 97.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 22.262 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å2-0 Å20.33 Å2
2--0.4 Å20 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 1.6→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3391 0 66 418 3875
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.023767
X-RAY DIFFRACTIONr_bond_other_d0.0020.023367
X-RAY DIFFRACTIONr_angle_refined_deg1.4431.9725172
X-RAY DIFFRACTIONr_angle_other_deg0.9293.0027848
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.365482
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.33224.04151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.39915564
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7311513
X-RAY DIFFRACTIONr_chiral_restr0.0780.2551
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214309
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02806
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.6894.0291865
X-RAY DIFFRACTIONr_mcbond_other2.674.0251864
X-RAY DIFFRACTIONr_mcangle_it4.0619.012362
X-RAY DIFFRACTIONr_mcangle_other4.0649.0132363
X-RAY DIFFRACTIONr_scbond_it3.6894.5621902
X-RAY DIFFRACTIONr_scbond_other3.6774.5631902
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.6119.8462809
X-RAY DIFFRACTIONr_long_range_B_refined7.53926.4794632
X-RAY DIFFRACTIONr_long_range_B_other7.53226.484632
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 180 -
Rwork0.269 3111 -
obs--95.84 %

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