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- SASDE54: Tryparedoxin W39A, in the presence of inhibitor CFT (2-(chloromet... -

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Basic information

Entry
Database: SASBDB / ID: SASDE54
SampleTryparedoxin W39A, in the presence of inhibitor CFT (2-(chloromethyl)-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one)
  • Tryparedoxin W39A (protein), Trypanosoma brucei brucei
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 / Thioredoxin-like superfamily
Similarity search - Domain/homology
Biological speciesTrypanosoma brucei brucei (eukaryote)
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.
Contact author
  • Martha Brennich (EMBL, European Molecular Biology Laboratory (EMBL) - Grenoble Outstation, Grenoble, France)

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Models

Model #2338
Type: atomic / Chi-square value: 1.87 / P-value: 0.000002
Search similar-shape structures of this assembly by Omokage search (details)
Model #2339
Type: atomic / Chi-square value: 1.87 / P-value: 0.000002
Search similar-shape structures of this assembly by Omokage search (details)

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Sample

SampleName: Tryparedoxin W39A, in the presence of inhibitor CFT (2-(chloromethyl)-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one)
BufferName: 10 mM HEPES pH 7.5, 50 mM NaCl / pH: 7.5
Entity #1271Type: protein / Description: Tryparedoxin W39A / Formula weight: 15.702 / Source: Trypanosoma brucei brucei / References: UniProt: O77404
Sequence:
GSGLAKYLPG ATNLLSKSGE VSLGSLVGKT VFLYFSASAC PPCRGFTPVL AEFYEKHHVA KNFEVVLISW DENESDFHDY YGKMPWLALP FDQRSTVSEL GKTFGVESIP TLITINADTG AIIGTQARTR VIEDPDGANF PWPN

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Experimental information

BeamInstrument name: ESRF BM29 / City: Grenoble / 国: France / Type of source: X-ray synchrotron / Wavelength: 0.099 Å / Dist. spec. to detc.: 2.869 mm
DetectorName: Pilatus 1M / Type: Dectris / Pixsize x: 172 mm
Scan
Title: Tryparedoxin W39A, in the presence of CFT / Measurement date: May 31, 2018 / Storage temperature: 20 °C / Cell temperature: 20 °C / Exposure time: 1 sec. / Unit: 1/nm /
MinMax
Q0.0373 4.9279
Distance distribution function P(R)
Sofotware P(R): GNOM 5.0 / Number of points: 922 /
MinMax
Q0.168674 4.49139
P(R) point1 922
R0 5.83
Result
Type of curve: sec
Comments: SEC column type: GE Healthcare S75 3.2/300; Sample Injection Concentration = 10 mg/mL; Column flow-rate = 0.1 mL/min.
ExperimentalPorod
MW15 kDa15 kDa
Volume-26.07 nm3

P(R)GuinierGuinier error
Forward scattering, I08.247 8.25 0.01
Radius of gyration, Rg1.6 nm1.6 nm0.01

MinMax
D-5.83
Guinier point29 165

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