aC helix displacement as a general approach for allosteric modulation of protein kinases

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The authors discuss the benefits of adopting an allosteric approach to perturb protein kinases, a class of molecule that is difficult to selectively modulate by other, more traditional approaches.

Owing to their crucial role in the modulation of cell pathways, protein kinases are important targets for several human diseases, including but not limited to cancer. The classic approach of targeting the ATP active site has recently come up against selectivity issues, which can be considerably reduced by following an allosteric modulation approach. Being closely related to protein kinase inactivation,

allosteric targeting via displacement of the conserved structural aC helix enables a direct and specific modulation mechanism. A structure-based survey of the allosteric regulation of aC helix conformation in various kinase families is provided, highlighting key allosteric pockets and modulation mechanismsthat appear to be more broadly conserved than was previously thought.

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