Abstract
Receptor tyrosine kinases (RTKs) are key regulators of normal cellular processes and have a critical role in the development and progression of many diseases. RTK ligand-induced stimulation leads to activation of the cytoplasmic kinase domain that controls the intracellular signalling. Although the kinase domain of RTKs has been extensively studied using X-ray analysis, the kinase insert domain (KID) and the C-terminal are partially or fully missing in all reported structures. We communicate the first structural model of the full-length RTK KIT cytoplasmic domain, a crucial target for cancer therapy. This model was achieved by integration of ab initio KID and C-terminal probe models into an X-ray structure, and by their further exploration through molecular dynamics (MD) simulation. An extended (2-µs) MD simulation of the proper model provided insight into the structure and conformational dynamics of the full-length cytoplasmic domain of KIT, which can be exploited in the description of the KIT transduction processes.
Highlights
A first vision of Receptor tyrosine kinases (RTKs) activation molecular mechanisms was developed from structural studies, principally performed by X-ray analysis[5,6]
The kinase insert domain (KID), which interrupts the kinase domain in the majority of RTKs (38 out of 58), was systematically deleted or replaced by a short pseudo-KID prior to crystallization of RTKs from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families, an option adapted from the in vitro studies showing that KID does not influence the kinase activity[10] and its deletion does not affect the overall structure of CD11 nor the binding of inhibitors in its active site[12]
We suggest that in KIT, the large KID and C-terminal may have an intrinsic folding and different positions with respect to the kinase domain, which would explain their absence in the crystal structures
Summary
A first vision of RTKs activation molecular mechanisms was developed from structural studies, principally performed by X-ray analysis[5,6]. Analysis of MD simulations of four candidate models built to represent the 3D structure of the full-length KIT cytoplasmic domain shows that the independent statistical techniques characterizing different structural metrics deliver coherent results.
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