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Assessing the Activation of Tyrosine Kinase KIT through Free Energy Calculations

[Image: see text] KIT is a type 3 receptor tyrosine kinase that plays a crucial role in cellular growth and proliferation. Mutations in KIT can dysregulate its active–inactive equilibrium. Activating mutations drive cancer growth, while deactivating mutations result in the loss of skin and hair pigm...

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Detalles Bibliográficos
Autores principales: Sandoval-Pérez, Angélica, Winger, Beth Apsel, Jacobson, Matthew P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558371/
https://www.ncbi.nlm.nih.gov/pubmed/36166736
http://dx.doi.org/10.1021/acs.jctc.2c00526
Descripción
Sumario:[Image: see text] KIT is a type 3 receptor tyrosine kinase that plays a crucial role in cellular growth and proliferation. Mutations in KIT can dysregulate its active–inactive equilibrium. Activating mutations drive cancer growth, while deactivating mutations result in the loss of skin and hair pigmentation in a disease known as piebaldism. Here, we propose a method based on molecular dynamics and free energy calculations to predict the functional effect of KIT mutations. Our calculations may have important clinical implications by defining the functional significance of previously uncharacterized KIT mutations and guiding targeted therapy.