Events in Physics

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.

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