Identification et exploitation des sites allostériques des caspases (conférence en anglais)

Description :

CONFÉRENCIÈRE : JEANNE A. HARDY, professeure associée, Département de chimie, Université du Massachusetts à Amherst, USA

Caspases, the cysteine proteases that initiate and control apoptotic cell death, are drug targets for diseases ranging from cancer to neurodegeneration. The most significant hurdle to their therapeutic use may be the overlapping active-site specificities for small molecule inhibitors, which do not fully reflect their true in vivo specificities for protein substrates. Thus, allosteric inhibition of individual caspases is appealing. Fortunately, caspases are extremely amenable to allosteric regulation due to their remarkably plastic substrate-binding grooves, which can be modulated by several distinct mechanisms. We have discovered allosteric sites in caspase-6 and -9 that are natively regulated by zinc and elucidated the molecular mechanism of inhibition crystallographically. We have identified other allosteric sites, unique to caspase-3, -6, -7, -8 or -9, respectively, that are controlled by phosphorylation. The mechanisms of allosteric inhibition at these sites predominantly center around distal control of the substrate-binding groove, which we have visualized using x-ray crystallography and biochemical analysis. Based on these inhibition mechanisms we have engineered an allosterically handcuffed version of caspase-7 that can be unlocked by the intracellular reduction potential. Finally, using specially-designed nanoparticles we have delivered caspases and induced apoptosis in cancer cells. Together these findings move us closer to therapeutically relevant control of caspases.