Discovery of Fragment Molecules That Bind the Human Peroxiredoxin 5 Active Site

The search for protein ligands is a crucial step in the inhibitor design process. Fragment screening represents an interesting method to rapidly find lead molecules, as it enables the exploration of a larger portion of the chemical space with a smaller number of compounds as compared to screening based on drug-sized molecules. Moreover, fragment screening usually leads to hit molecules that form few but optimal interactions with the target, thus displaying high ligand efficiencies. Here we report the screening of a homemade library composed of 200 highly diverse fragments against the human Peroxiredoxin 5 protein. Peroxiredoxins compose a family of peroxidases that share the ability to reduce peroxides through a conserved cysteine. The three-dimensional structures of these enzymes ubiquitously found throughout evolution have been extensively studied, however, their biological functions are still not well understood and to date few inhibitors have been discovered against these enzymes. Six fragments from the library were shown to bind to the Peroxiredoxin 5 active site and ligand-induced chemical shift changes were used to drive the docking of these small molecules into the protein structure. The orientation of the fragments in the binding pocket was confirmed by the study of fragment homologues, highlighting the role of hydroxyl functions that hang the ligands to the Peroxiredoxin 5 protein. Among the hit fragments, the small catechol molecule was shown to significantly inhibit Peroxiredoxin 5 activity in a thioredoxin peroxidase assay. This study reports novel data about the ligand-Peroxiredoxin interactions that will help considerably the development of potential Peroxiredoxin inhibitors

Relationships among Cichorium species and related genera as determined by analysis of mitochondrial RFLPs

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Sequence and transcript analysis of the Nco2.5 Ogura-specific fragment correlated with cytoplasmic male sterility in Brassica cybrids

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NMR structures of thioredoxin m from the green alga Chlamydomonas reinhardtii

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The strange evolutionary history of plant mitochondrial tRNAs and their aminoacyl-tRNA synthetases

International audienceThe translation systems of plant mitochondria differ from those of other mitochon-dria in that they incorporate tRNAs of three different origins: native mitochondrial tRNAs, plastid tRNAs transcribed from plastid DNA insertions in mitochondrial DNA, and nuclearly encoded imported tRNAs. The complicated evolutionary history of the tRNA replacement events leading up to this situation is slowly being unrav-eled. Recent research on plant aminoacyl-tRNA synthetases is starting to reveal how the mitochondrial compartment can cope with this unusual mix of tRNAs and has uncovered an unprecedented degree of sharing of isoforms between compart-ments. Many plant aminoacyl-tRNA synthetases are dual targeted to two compart-ments, either cytosol/mitochondria or plastids/mitochondria. The molecular basis for some of these cases of dual targeting are described