7b02 | pdb_00007b02

Thioredoxin glutathione reductase from Schistosoma mansoni in complex with 4-Hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid

spinqualitylabelsall models 7b02, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7b02 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 1.45Å Ligands: CL, DMS, FAD, K, NA, PEG, SJN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A3Q0KFL1_SCHMA Publication Abstract from PubMed Fragment screening is a powerful drug discovery approach particularly useful for enzymes difficult to inhibit selectively, such as the thiol/selenol-dependent thioredoxin reductases (TrxRs), which are essential and druggable in several infectious diseases. Several known inhibitors are reactive electrophiles targeting the selenocysteine-containing C-terminus and thus often suffering from off-target reactivity in vivo. The lack of structural information on the interaction modalities of the C-terminus-targeting inhibitors, due to the high mobility of this domain and the lack of alternative druggable sites, prevents the development of selective inhibitors for TrxRs. In this work, fragments selected from actives identified in a large screen carried out against Thioredoxin Glutathione Reductase from Schistosoma mansoni (SmTGR) were probed by X-ray crystallography. SmTGR is one of the most promising drug targets for schistosomiasis, a devastating, neglected disease. Utilizing a multicrystal method to analyze electron density maps, structural analysis, and functional studies, three binding sites were characterized in SmTGR: two sites are close to or partially superposable with the NADPH binding site, while the third one is found between two symmetry related SmTGR subunits of the crystal lattice. Surprisingly, one compound bound to this latter site stabilizes, through allosteric effects mediated by the so-called guiding bar residues, the crucial redox active C-terminus of SmTGR, making it finally visible at high resolution. These results further promote fragments as small molecule probes for investigating functional aspects of the target protein, exemplified by the allosteric effect on the C-terminus, and providing fundamental chemical information exploitable in drug discovery. Probing the Surface of a Parasite Drug Target Thioredoxin Glutathione Reductase Using Small Molecule Fragments.,Fata F, Silvestri I, Ardini M, Ippoliti R, Di Leandro L, Demitri N, Polentarutti M, Di Matteo A, Lyu H, Thatcher GRJ, Petukhov PA, Williams DL, Angelucci F ACS Infect Dis. 2021 May 5. doi: 10.1021/acsinfecdis.0c00909. PMID:33950676 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thioredoxin Glutathione Reductase

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