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Unveiling the Transient Protein-Protein Interactions that Regulate the Activity of Human Lemur Tyrosine Kinase-3 (LMTK3) Domain by Cyclin Dependent Kinase 5 (CDK5) in Breast Cancer: An in silico Study

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Background: In many human diseases protein kinase are known to play a central role. Protein kinases phosphorylate its substrates and they themselves regulated through phosphorylation of their activation loop and become catalytically active. LMTK3 is an oncogenic protein kinase, implicated in breast cancer progression and endocrine resistance. Recent report says phosphorylation of LMTK3 by CDK5 results in breast cancer tumor progression. Thereby information about interface residues and probable phosphorylation site on LMTK3 is critical.

Objective: To understand the transient protein – protein interactions between CDK5 and LMTK3 using computational techniques.

Methods: LMTK3 structure was superimposed with known kinases to determine the probable activation segment and phosphorylation sites in LMTK3. PatchDock was used to obtain CDK5-LMTK3 complex structure. PDBsum server was used to identify the interface residues between CDK5 and LMTK3. The stability of CDK5-LMTK3 complex was studied using Molecular dynamics (MD) simulation.

Results: From PatchDock, interface area between CDK5-LMTK3 complex was found to be 2081 Ų with atomic contact energy of -228.80 kcal/mol. PDBsum result reveal that, CDK5 interact and displayed non-bonding interactions with the probable phosphorylation sites of LMTK3. Total number of interface residues across CDK5-LMTK3 was found to be around 50 and the interface area found to be 1274 Ų (in CDK5) and 1224 Ų (in LMTK3). From MD simulation, CDK5-LMTK3 complex was found to be stable.

Conclusion: This study enhances the understanding of interactions between CDK5 and LMTK3 that may be helpful in understanding the LMTK3 phosphorylation by CDK5 which is considered to be a new cellular pathway in breast cancer tumor progression.
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Keywords: Breast cancer progression; PDBsum; PatchDock; activation segment; molecular dynamics simulation; phosphorylation sites

Document Type: Research Article

Publication date: February 1, 2018

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