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.
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| Author: | Deep ChatterjeeORCiDGND, Franziska Friederike PreussGND, Verena DedererGND, Stefan KnappORCiD, Sebastian MatheaORCiD |
|---|---|
| URN: | urn:nbn:de:hebis:30:3-818834 |
| DOI: | https://doi.org/10.3390/cells11010142 |
| ISSN: | 2073-4409 |
| Parent Title (English): | Cells |
| Publisher: | MDPI |
| Place of publication: | Basel |
| Document Type: | Article |
| Language: | English |
| Date of Publication (online): | 2022/01/02 |
| Date of first Publication: | 2022/01/02 |
| Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
| Release Date: | 2024/02/14 |
| Tag: | LIMK1; LIMK2; actin cytoskeleton dynamics; catalytic mechanism; cofilin; kinase; phosphorylation; small-molecule inhibitor |
| Volume: | 11 |
| Issue: | 1, art. 142 |
| Article Number: | 142 |
| Page Number: | 12 |
| First Page: | 1 |
| Last Page: | 12 |
| Note: | The authors are grateful for support by the SGC, a registered charity (no. 1097737) that receives funds from AbbVie, BayerAG, Boehringer Ingelheim, the Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510]. |
| Institutes: | Biochemie, Chemie und Pharmazie |
| Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS) | |
| Sammlungen: | Universitätspublikationen |
| Licence (German): |  Creative Commons - CC BY - Namensnennung 4.0 International |
