Structural studies of full-length receptor tyrosine kinases and their implications for drug design

Abstract

Receptor tyrosine kinases (RTKs) are important drug targets for cancer and immunological disorders. Crystal structures of individual RTK domains have contributed greatly to the structure-based drug design of clinically used drugs. Low-resolution structures from electron microscopy are now available for the RTKs, EGFR, PDGFR, and Kit. However, there are still no high-resolution structures of full-length RTKs due to the technical challenges of working with these complex, membrane proteins. Here, we review what has been learned from structural studies of these three RTKs regarding their mechanisms of ligand binding, activation, oligomerization, and inhibition. We discuss the implications for drug design. More structural data on full-length RTKs may facilitate the discovery of druggable sites and drugs with improved specificity and effectiveness against resistant mutants.

Keywords: Drug design; EGFR; Kinase inhibitors; Kinases; Kit; PDGFR; Receptor kinases; Structural biology; Tyrosine kinases.