6fmu

Thioredoxin glutathione reductase from Schistosome mansoni in complex with 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol

spinqualitylabelsall models 6fmu, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fmu is a 1 chain structure with sequence from Schistosoma mansoni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: DVK, FAD, PGE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases. Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry.,Silvestri I, Lyu H, Fata F, Boumis G, Miele AE, Ardini M, Ippoliti R, Bellelli A, Jadhav A, Lea WA, Simeonov A, Chen Q, Arner ESJ, Thatcher GR, Petukhov PA, Williams DL, Angelucci F ACS Chem Biol. 2018 May 25. doi: 10.1021/acschembio.8b00349. PMID:29800515 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thioredoxin Glutathione Reductase

Proteopedia Page Contributors and Editors (what is this?)

OCA