LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique 'rock-and-poke' mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding.
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| http://dx.doi.org/10.1042/BCJ20190517 | DOI Listing |
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Article Synopsis
- Microtubule dysfunction is linked to neurodegenerative disorders like Parkinson's disease, but it's unclear if it's a cause or a symptom of the disease.
- Recent research identified that LIMK1 plays a key role in regulating the neuronal cytoskeleton and microtubule dynamics, particularly after traumatic brain injury.
- The study found that increasing LIMK1 expression correlates with dopaminergic neuron death in a Parkinson's model and that using a LIMK inhibitor successfully reversed this neurodegeneration, suggesting targeting microtubules could be a viable treatment strategy.
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