6rtj | pdb_00006rtj

Thioredoxin glutathione reductase from Schistosoma mansoni in complex with 1-[(dimethylamino)methyl]-2-naphthol at 1 hour of soaking

spinqualitylabelsall models 6rtj, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6rtj is a 1 chain structure with sequence from Blood fluke. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, FAD, FXH, PG4, PGE Gene: Smp_048430 (Blood fluke) Activity: Thioredoxin-disulfide reductase, with EC number 1.8.1.9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Selective suicide inhibitors represent a seductively attractive approach for inactivation of therapeutically relevant enzymes since they are generally devoid of off-target toxicity in vivo. While most suicide inhibitors are converted to reactive species at enzyme active sites, theoretically bioactivation can also occur in ectopic (secondary) sites that have no known function. Here, we report an example of such an "ectopic suicide inhibition", an unprecedented bioactivation mechanism of a suicide inhibitor carried out by a non-catalytic site of thioredoxin glutathione reductase (TGR). TGR is a promising drug target to treat schistosomiasis, a devastating human parasitic disease. Utilizing hits selected from a high throughput screening campaign, time-resolved X-ray crystallography, molecular dynamics, mass spectrometry, molecular modeling, protein mutagenesis and functional studies, we find that 2-naphtholmethylamino derivatives bound to this novel ectopic site of Schistosoma mansoni (Sm)TGR are transformed to covalent modifiers and react with its mobile selenocysteine-containing C-terminal arm. In particular, one 2-naphtholmethylamino compound is able to specifically induce the pro-oxidant activity in the inhibited enzyme. Since some 2-naphtholmethylamino analogues show worm killing activity and the ectopic site is not conserved in human orthologues, a general approach to development of novel and selective anti-parasitic therapeutics against schistosoma is proposed. Ectopic suicide inhibition of thioredoxin glutathione reductase.,Silvestri I, Lyu H, Fata F, Banta PR, Mattei B, Ippoliti R, Bellelli A, Pitari G, Ardini M, Petukhova V, Thatcher GRJ, Petukhov PA, Williams DL, Angelucci F Free Radic Biol Med. 2020 Feb 1;147:200-211. doi:, 10.1016/j.freeradbiomed.2019.12.019. Epub 2019 Dec 20. PMID:31870799 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thioredoxin Glutathione Reductase

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