Receptor Tyrosine Kinases DimerizationReceptor tyrosine kinases undergo ligand dependent dimerization, which activates their intrinsic protein tyrosine kinase (PTK) domains. We have determined the crystal structure of Stem cell factor (SCF) and fibroblast growth factor (FGF), two ligands of receptor tyrosine kinases. The crystal structures of FGF in complex with the extracellular ligand-binding domain of FGF-receptor (FGFR) and with a heparin sulfate oligosaccharide were also determined. The structure of the ternary FGF/heparin/FGFR complex provides a molecular view of how FGF acts in concert with heparin to induce the dimerization and activation of FGF-receptors. We have also determined the crystal structure of the catalytic PTK domain of FGFR in complex with an ATP analogue or in complex with specific PTK inhibitors of FGFR activity and function.
Development of Specific Inhibitor for PTKs
These structures enabled the development of new specific inhibitor for PTKs that are currently being tested in clinical trials. Receptor tyrosine kinases undergo ligand-dependent dimerization, which activates their intrinsic protein tyrosine kinase activity resulting in autophosphorylation and subsequent interaction and recruitment of multiple cellular target proteins. The phospho rylated tyrosine residues together with their immediate flanking sequences function as binding sites for signaling molecules containing src homology 2 (SH2) domains. Many signaling proteins carry SH2 domains plus one or more small protein modules such as SH3, PH, PTB, WW or FYVE domains. These protein modules function as mediator of protein-protein or protein-lipid interactions that are critical for signal transmission.