6FMZ
Thioredoxin glutathione reductase from Schistosoma mansoni in complex with 1,4-Bis(2-hydroxyethyl)piperazine
Summary for 6FMZ
| Entry DOI | 10.2210/pdb6fmz/pdb |
| Descriptor | Thioredoxin glutathione reductase, FLAVIN-ADENINE DINUCLEOTIDE, 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanol, ... (4 entities in total) |
| Functional Keywords | fragment, allosteric pocket, schistosomiasis, fad/nad linked reductase, flavoprotein |
| Biological source | Schistosoma mansoni (Blood fluke) |
| Total number of polymer chains | 1 |
| Total formula weight | 66020.94 |
| Authors | Silvestri, I.,Fata, F.,MIele, A.E.,Boumis, G.,Williams, D.L.,Angelucci, F. (deposition date: 2018-02-02, release date: 2018-06-06, Last modification date: 2024-10-09) |
| Primary citation | Silvestri, I.,Lyu, H.,Fata, F.,Boumis, G.,Miele, A.E.,Ardini, M.,Ippoliti, R.,Bellelli, A.,Jadhav, A.,Lea, W.A.,Simeonov, A.,Cheng, Q.,Arner, E.S.J.,Thatcher, G.R.J.,Petukhov, P.A.,Williams, D.L.,Angelucci, F. Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry. ACS Chem. Biol., 13:2190-2202, 2018 Cited by PubMed Abstract: 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 selectively 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. PubMed: 29800515DOI: 10.1021/acschembio.8b00349 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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