Analysis of HSP90-related folds with MED-SuMo classification approach

Three-dimensional structural information is critical for understanding functional protein properties and the precise mechanisms of protein functions implicated in physiological and pathological processes. Comparison and detection of protein binding sites are key steps for annotating structures with functional predictions and are extremely valuable steps in a drug design process. In this research area, MED-SuMo is a powerful technology to detect and characterize similar local regions on protein surfaces. Each amino acid residue’s potential chemical interactions are represented by specific surface chemical features (SCFs). The MED-SuMo heuristic is based on the representation of binding sites by a graph structure suitable for exploration by an efficient comparison algorithm. We use this approach to analyze one particular SCOP superfamily which includes HSP90 chaperone, MutL/DNA topoisomerase, histidine kinases, and α-ketoacid dehydrogenase kinase C (BCK). They share a common fold and a common region for ATP-binding. To analyze both similar and differing features of this fold, we use a novel classification method, the MED-SuMo multi approach (MED-SMA). We highlight common and distinct features of these proteins. The different clusters created by MED-SMA yield interesting observations. For instance, one cluster gathers three types of proteins (HSP90, topoisomerase VI, and BCK) which all bind the drug radicicol

Computational fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding site

International audienceEg5, a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle has attracted interest as an anticancer drug target. Eg5 is co-crystallized with several inhibitors bound to its allosteric binding pocket. Each of these occupies a pocket formed by loop 5/helix alpha2 (L5/alpha2). Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. The goal of the present study was to explore this hydrophobic pocket with our MED-SuMo fragment-based protocol, and thus discover novel chemical structures that might bind as inhibitors. The MED-SuMo software is able to compare and superimpose similar interaction surfaces upon the whole protein data bank (PDB). In a fragment-based protocol, MED-SuMo retrieves MED-Portions that encode protein-fragment binding sites and are derived from cross-mining protein-ligand structures with libraries of small molecules. Furthermore we have excluded intra-family MED-Portions derived from Eg5 ligands that occupy the hydrophobic pocket and predicted new potential ligands by hybridization that would fill simultaneously both pockets. Some of the latter having original scaffolds and substituents in the hydrophobic pocket are identified in libraries of synthetically accessible molecules by the MED-Search software

NMReDATA, a standard to report the NMR assignment and parameters of organic compounds

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Open access articleEven though NMR has found countless applications in the field of small molecule characterization, there is no standard file for the NMR data relevant to structure characterization of small molecules. A file format is introduced to associate the NMR parameters extracted from 1D and 2D spectra of organic compounds to the assigned chemical structure. These NMR parameters, which we shall call NMReDATA, include chemical shift values, signal integrals, intensities, multiplicities, scalar coupling constants, lists of 2D correlations, relaxation times and diffusion rates. The file format is an extension of the existing SDF (Structure Data Format), which is compatible with the commonly used MOL format. The association of an NMReDATA file with the raw and spectral data from which it originates constitutes an NMR record. This format is easily readable by humans and computers and provides a simple and efficient way for disseminating results of structural chemistry investigations, automating the verification of published result, and for assisting the constitution of highly needed open-source structural databases

De la simple famille paternelle en droit romain ... Première ptie. avec 14 figures

"Mémoire publié à l'occasion du jubilé de l'Université de Genéve: 1559-1909."Mode of access: Internet