Structural Aspects of LIMK Regulation and Pharmacology

Malfunction of the actin cytoskeleton is linked to numerous human diseases including neurological disorders and cancer. LIMK1 (LIM domain kinase 1) and its paralogue LIMK2 are two closely related kinases that control actin cytoskeleton dynamics. Consequently, they are potential therapeutic targets for the treatment of such diseases. In the present review, we describe the LIMK conformational space and its dependence on ligand binding. Furthermore, we explain the unique catalytic mechanism of the kinase, shedding light on substrate recognition and how LIMK activity is regulated. The structural features are evaluated for implications on the drug discovery process. Finally, potential future directions for targeting LIMKs pharmacologically, also beyond just inhibiting the kinase domain, are discussed.

Automated summary

This review focuses on the regulation of actin cytoskeleton dynamics by LIMKs and their potential therapeutic applications in diseases such as neurological disorders and cancer. It provides a comprehensive understanding of the LIMK conformational space, its catalytic mechanism, and the regulation of its activity, shedding light on substrate recognition. The implications of these structural features on drug discovery are also discussed, along with potential future directions for targeting LIMKs beyond kinase inhibition.