2025/01/01 by Saleena Younus, Özge Tatlı, Ahmad Nasimian +2 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Hemoglobinopathies and Related Disorders #Nuclear Structure and Function
paper · doi:10.1016/j.csbj.2025.10.023
openalex publication_date 2025/01/01 · openalex created_date 2025/10/15 · openalex updated_date 2026/07/23
include point mutations or deletions in the tyrosine kinase domain (TKD) and internal tandem duplications (ITD) in the juxtamembrane (JM) region. These mutations lead to ligand-independent activation, disrupting the JM region and kinase domain interaction, resulting in autophosphorylation of FLT3 and activation of signalling pathways such as STAT5, MAPK, and AKT, which promotes increased proliferation and resistance to apoptosis. So developing effective therapeutics against these mutant FLT3 proteins is crucial for AML treatment. Here we employed computational approaches, including Molecular Dynamics (MD) simulation, cluster analysis, and Normal Mode Analysis, to investigate the dynamic behaviours of FLT3 mutant structures (TKD mutants Y842C/F in FLT3-WT, FLT3- ITD, and ITD mutant in FLT3-WT). The molecular dynamics (MD) simulation studies revealed that all these mutations significantly affect the optimized state, flexibility, and compactness of the FLT3 protein. Cluster analysis also confirmed that these mutations significantly impacted protein flexibility. Specifically, the ITD mutation in the JM region increased the overall flexibility of the FLT3 structure, whereas the point mutations in the TKD domain (TKD; Y842C and Y842F) and the combined mutations of ITD and TKD in the FLT3 protein (ITD + Y842C/F) resulted in more rigid conformations. These findings highlight the distinct conformational effects of FLT3 mutations that contribute to kinase deregulation and underscore their potential as therapeutic targets in AML.