Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str 15, 60438 Frankfurt am Main, Germany.
Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str 9, 60438 Frankfurt am Main, Germany.
Cells. 2022 Jan 2;11(1):142. doi: 10.3390/cells11010142.
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.
肌动蛋白细胞骨架的功能障碍与许多人类疾病有关，包括神经紊乱和癌症。LIMK1（LIM 结构域激酶 1）及其同源物 LIMK2 是两种密切相关的激酶，它们控制肌动蛋白细胞骨架的动态。因此，它们是治疗此类疾病的潜在治疗靶点。在本综述中，我们描述了 LIMK 的构象空间及其对配体结合的依赖性。此外，我们解释了激酶独特的催化机制，阐明了底物识别以及 LIMK 活性如何受到调节。我们评估了这些结构特征对药物发现过程的影响。最后，讨论了针对 LIMK 进行药理学靶向的潜在未来方向，不仅限于抑制激酶结构域。
