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Francesco Gervasio, UCL

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Location: PS1.28

Conformational changes and allosteric control of protein-kinases

Protein kinases (PK) show a remarkable conformational dynamics that is tightly regulated in physiological conditions, often by allosteric signals. A shift of the conformational ensemble towards the active state, with the consequent hyper-activation of the PK, leads to a number of human diseases, including cancer. Thus, understanding how allosteric signals regulate the inactive to active equilibrium in PK could lead to the rational design of a new class of allosteric drugs. Historically, drug discovery programs have been dominated by efforts to develop antagonists that compete for binding with endogenous ligands at orthosteric sites. However, allosteric drugs might offer several therapeutic advantages over traditional orthosteric ligands, including greater safety and/or selectivity. Here, by combining state-of-the-art computer simulations with spectroscopy, chemical and molecular biology approaches we study in great details the role of conformational changes and oncogenic mutations in the allosteric control of pharmaceutically relevant kinases such as: cAbl, EGFR and FGFr.

1. S. Lovera, L. Sutto, R. Boubeva, L. Scapozza, N. Doelker and F. L. Gervasio* The different flexibility of c-Src and c-Abl kinases regulates the stability of the DFG-out inactive state J. Am. Chem. Soc., 134 2496^?2499, 2012; 2. F. Bono, et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties, Cancer Cell, 23, 477-488, 2013; 3. C. Herbert, et al. Molecular mechanism of SSR128129E, an extracellularly acting small molecule allosteric inhibitor of FGF receptor signaling, Cancer Cell, 23, 489-501, 2013; 4. L. Sutto and F. L. Gervasio The effect of oncogenic mutations on the conformational free energy landscape of the EGFR kinase. Proc Natnl Aca Sci USA, in press

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