期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 20, 页码 -出版社
MDPI
DOI: 10.3390/ijms222010986
关键词
protein-protein interaction; kinase inhibitors; cancer therapy; neurodegenerative diseases; molecular dynamics simulation; microtubule dynamics
资金
- Taif University Researchers Supporting Project [TURSP-2020/131]
- Council of Scientific and Industrial Research [27(0368)/20/EMR-II]
- NRF (National Research Foundation)
- Department of Science and Technology, Government of India [SR/FST/LSII/2020/782]
The study demonstrates that irisin binds to MARK4 and inhibits its activity, providing a new therapeutic approach for MARK4-associated diseases.
Irisin is a clinically significant protein playing a valuable role in regulating various diseases. Irisin attenuates synaptic and memory dysfunction, highlighting its importance in Alzheimer's disease. On the other hand, Microtubule Affinity Regulating Kinase 4 (MARK4) is associated with various cancer types, uncontrolled neuronal migrations, and disrupted microtubule dynamics. In addition, MARK4 has been explored as a potential drug target for cancer and Alzheimer's disease therapy. Here, we studied the binding and subsequent inhibition of MARK4 by irisin. Irisin binds to MARK4 with an admirable affinity (K = 0.8 x 10(7) M-1), subsequently inhibiting its activity (IC50 = 2.71 mu m). In vitro studies were further validated by docking and simulations. Molecular docking revealed several hydrogen bonds between irisin and MARK4, including critical residues, Lys38, Val40, and Ser134. Furthermore, the molecular dynamic simulation showed that the binding of irisin resulted in enhanced stability of MARK4. This study provides a rationale to use irisin as a therapeutic agent to treat MARK4-associated diseases.
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