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

Contacts cellulaires des fibres myélinisées du système nerveux périphérique

La myélinisation permet la propagation rapide des potentiels d'action. Elle fournit à l'axone une gaine de myéline isolante régulièrement interrompue au niveau des noeuds de Ranvier où sont concentrés les canaux Na+ dépendants du voltage. Dans le système nerveux périphérique, l'architecture et la fonction des fibres myélinisées sont dépendantes de l'établissement de contacts cellulaires finement régulés, entre les membranes d'une même cellule gliale myélinisante, entre l'axone et les cellules gliales, et entre les cellules gliales et la matrice extracellulaire. Des composants protéiques majeurs de l'ensemble de ces contacts ont été identifiés ces dernières années. Cette revue résume les connaissances actuelles dans ce domaine

Arpin Regulates Migration Persistence by Interacting with Both Tankyrases and the Arp2/3 Complex

International audienc

The Arp1/11 minifilament of dynactin primes the endosomal Arp2/3 complex

Dendritic actin networks develop from a first actin filament through branching by the Arp2/3 complex. At the surface of endosomes, the WASH complex activates the Arp2/3 complex and interacts with the capping protein for unclear reasons. Here, we show that the WASH complex interacts with dynactin and uncaps it through its FAM21 subunit. In vitro, the uncapped Arp1/11 minifilament elongates an actin filament, which then primes the WASH-induced Arp2/3 branching reaction. In dynactin-depleted cells or in cells where the WASH complex is reconstituted with a FAM21 mutant that cannot uncap dynactin, formation of branched actin at the endosomal surface is impaired. Our results reveal the importance of the WASH complex in coordinating two complexes containing actin-related proteins