Abstract
Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed.
Highlights
None of the TAM kinase 3D structures was solved in the DFG-Asp out conformation; they were built by homology modeling using as template the phylogenetically-related tyrosine kinase c-Met in this conformation (PDB ID: 3F82 [47])
We show here the set of amino acids encompassed at 6 Å for each TAM kinase model in the DFG-Asp in (Figure 5a) and the DFG-Asp out (Figure 5b) conformations
Similar steric constraints are observed for the 5-chloride group in compounds 91 and 97 when either ligand is docked inside the Tyro-3 model and subsequently overlapped with the Axl and Mer homology models
Summary
Kinases are ubiquitous enzymes from the transferase family. Protein kinases catalyze the covalent transfer of a phosphoryl group from ATP to a substrate, which can be another protein (e.g., another kinase), a lipid or a nucleic acid. Protein kinases are the largest family of kinases, encompassing 518 members (as currently identified in the human genome) [1]. Their catalytic domain is well conserved and features a common set of crucial amino acids. One interesting class of protein kinases are receptor tyrosine kinases (RTKs), transmembrane proteins that transmit signals from the extracellular medium to the cytoplasm and nucleus. They are fundamental for basic life functions, as they regulate many cellular processes such as survival, growth, differentiation, adhesion and motility. Dysfunction or deregulation of certain kinases can lead to diseases such as cancer; these enzymes have garnered enormous interest as therapeutic targets
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