6i7n

Trypanothione Reductase from Leismania infantum in complex with TRL156

spinqualitylabelsall models 6i7n, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6i7n is a 2 chain structure with sequence from Leishmania infantum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.3Å Ligands: FAD, GOL, H6H, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A4HSF7_LEIIN Publication Abstract from PubMed Disruption of protein-protein interactions of essential oligomeric enzymes by small molecules represents a significant challenge. We recently reported some linear and cyclic peptides derived from an alpha-helical region present in the homodimeric interface of Leishmania infantum trypanothione reductase ( Li-TryR) that showed potent effects on both dimerization and redox activity of this essential enzyme. Here, we describe our first steps toward the design of nonpeptidic small-molecule Li-TryR dimerization disruptors using a proteomimetic approach. The pyrrolopyrimidine and the 5-6-5 imidazole-phenyl-thiazole alpha-helix-mimetic scaffolds were suitably decorated with substituents that could mimic three key residues (K, Q, and I) of the linear peptide prototype (PKIIQSVGIS-Nle-K-Nle). Extensive optimization of previously described synthetic methodologies was required. A library of 15 compounds bearing different hydrophobic alkyl and aromatic substituents was synthesized. The imidazole-phenyl-thiazole-based analogues outperformed the pyrrolopyrimidine-based derivatives in both inhibiting the enzyme and killing extracellular and intracellular parasites in cell culture. The most active imidazole-phenyl-thiazole compounds 3e and 3f inhibit Li-TryR and prevent growth of the parasites at low micromolar concentrations similar to those required by the peptide prototype. The intrinsic fluorescence of these compounds inside the parasites visually demonstrates their good permeability in comparison with previous peptide-based Li-TryR dimerization disruptors. Pyrrolopyrimidine vs Imidazole-Phenyl-Thiazole Scaffolds in Nonpeptidic Dimerization Inhibitors of Leishmania infantum Trypanothione Reductase.,Revuelto A, Ruiz-Santaquiteria M, de Lucio H, Gamo A, Carriles AA, Gutierrez KJ, Sanchez-Murcia PA, Hermoso JA, Gago F, Camarasa MJ, Jimenez-Ruiz A, Velazquez S ACS Infect Dis. 2019 Apr 23. doi: 10.1021/acsinfecdis.8b00355. PMID:30983322 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Trypanothione reductase

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