6spt

High resolution crystal structure of N-terminal domain of PEX14 from Trypanosoma brucei in complex with the fist compound with sub-micromolar trypanocidal activity

spinqualitylabelsall models 6spt, resolution 1.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6spt is a 1 chain structure with sequence from Trypanosoma brucei brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.2Å Ligands: BME, CL, FTW Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8IEW2_TRYBB Publication Abstract from PubMed Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 protein-protein interaction. The optimization was driven by several X-ray structures, NMR binding data and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen T. brucei gambiense and T. cruzi parasites. Structure-activity relationship in pyrazolo[4,3-c]pyridines, first inhibitors of PEX14-PEX5 Protein-Protein Interaction (PPI) with trypanocidal activity.,Dawidowski M, Kalel VC, Napolitano V, Fino R, Schorpp K, Emmanouilidis L, Lenhart D, Ostertag M, Kaiser M, Kolonko M, Tippler B, Schliebs W, Dubin G, Maser P, Tetko I, Hadian K, Plettenburg O, Erdmann R, Sattler M, Popowicz GM J Med Chem. 2019 Dec 20. doi: 10.1021/acs.jmedchem.9b01876. PMID:31860309 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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