Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors

Molecules. 2014 Oct 10;19(10):16223-39. doi: 10.3390/molecules191016223.

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.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Catalytic Domain
  • Drug Design
  • Drug Discovery
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Phosphotransferases
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / chemistry*
  • Sequence Alignment

Substances

  • Protein Kinase Inhibitors
  • Phosphotransferases
  • Receptor Protein-Tyrosine Kinases