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Yorodumi- PDB-8a1r: cryo-EM structure of thioredoxin glutathione reductase in complex... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8a1r | ||||||
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Title | cryo-EM structure of thioredoxin glutathione reductase in complex with a non-competitive inhibitor | ||||||
Components | Thioredoxin glutathione reductase | ||||||
Keywords | FLAVOPROTEIN / inhibitor / complex / flavoreductase | ||||||
Function / homology | Function and homology information thioredoxin-disulfide reductase / thioredoxin-disulfide reductase (NADPH) activity / cell redox homeostasis / flavin adenine dinucleotide binding / metal ion binding Similarity search - Function | ||||||
Biological species | Schistosoma mansoni (invertebrata) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | ||||||
Authors | Ardini, M. / Angelucci, F. / Fata, F. / Gabriele, F. / Effantin, G. / Ling, W. / Williams, D.L. / Petukhova, V.Z. / Petukhov, P.A. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Commun / Year: 2023 Title: Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo. Authors: Valentina Z Petukhova / Sammy Y Aboagye / Matteo Ardini / Rachel P Lullo / Francesca Fata / Margaret E Byrne / Federica Gabriele / Lucy M Martin / Luke N M Harding / Vamshikrishna Gone / ...Authors: Valentina Z Petukhova / Sammy Y Aboagye / Matteo Ardini / Rachel P Lullo / Francesca Fata / Margaret E Byrne / Federica Gabriele / Lucy M Martin / Luke N M Harding / Vamshikrishna Gone / Bikash Dangi / Daniel D Lantvit / Dejan Nikolic / Rodolfo Ippoliti / Grégory Effantin / Wai Li Ling / Jeremy J Johnson / Gregory R J Thatcher / Francesco Angelucci / David L Williams / Pavel A Petukhov / Abstract: Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from ...Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8a1r.cif.gz | 205.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8a1r.ent.gz | 170 KB | Display | PDB format |
PDBx/mmJSON format | 8a1r.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/a1/8a1r ftp://data.pdbj.org/pub/pdb/validation_reports/a1/8a1r | HTTPS FTP |
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-Related structure data
Related structure data | 15084MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 65061.145 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Schistosoma mansoni (invertebrata) / Gene: TGR / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q962Y6, EC: 1.6.4.5 #2: Chemical | #3: Chemical | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component |
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Molecular weight |
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Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 / Details: filtered aqueous fresh solution | |||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: Mono-dispersed TGR molecules in aqueous sample buffer containing DMSO and inhibitor | |||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | |||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293.15 K / Details: Blotting time= 7s, wait time= 10 s |
-Electron microscopy imaging
Microscopy | Model: TFS GLACIOS / Details: Manual preliminar screening |
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: SPOT SCAN |
Electron lens | Mode: DIFFRACTION / Nominal magnification: 12000 X / Nominal defocus max: 2600 nm / Nominal defocus min: 1800 nm / Cs: 2.7 mm / C2 aperture diameter: 150 µm / Alignment procedure: BASIC |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2600 |
Image scans | Movie frames/image: 50 / Used frames/image: 1-50 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 1479588 | |||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | |||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173572 / Symmetry type: POINT | |||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | |||||||||||||||||||||||||||
Atomic model building | PDB-ID: 2V6O |