Salient Structural Features of Human Lemur Tyrosine Kinase 3 (LMTK3) Domain from Molecular Dynamics Simulation Study

Background: Estrogen receptor-α (ERα) positive breast cancer is considered to be one of the most common metastatic diseases. Estrogenic signalling in breast cancer is one of the most critical oncogenic pathways. Recently Lemur Tyrosine Kinase 3 (LMTK3) was identified as a potential oncogenic ERα regulator with a significant role in endocrine resistance. Therefore, targeting LMTK3 in breast cancer would control ERα modulation and may provide a better diagnostic development and a new therapeutic target to fight these resistant and aggressive tumours. Objective: The study aimed to understand the salient structural features of LMTK3 using molecular dynamics simulation. Methods: In this computational study, we modelled 3D structure of LMTK3 domain using Iterative Threading ASSembly Refinement (I-TASSER) and studied conformational dynamics using molecular dynamics simulation. We used online computational tools and software to perform comprehensive investigation on the cavities, hydrophobicity, electrostatic potential, secondary structure topology and intra- molecular interactions in LMTK3. Results: The LMTK3 structure was observed to be stable during Molecular Dynamics (MD) simulation. We also predicted the probable binding cavities in LMTK3. In addition, we determined hydrophobic clusters and patches in LMTK3 which may be crucial for folding and stabilisation. Possible interaction sites in LMTK3 were then studied by electrostatic potential analysis based on positive and negative surfaces. From the secondary structure topology analysis, we noticed nine antiparallel β-sheets forming β- sheets topology and five hairpins were involved in forming the secondary structure. Conclusion: Our inferences from this study would be helpful in understanding the structure–function relationships of LMTK3 and also help in designing suitable inhibitors for LMTK3.