Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases

Receptor tyrosine kinases (RTKs) orchestrate embryonic development and tissue homeostasis by controlling key cellular processes like growth proliferation. Consequently, the vast majority of 58 RTKs in humans are linked to cancer or metabolic disorders. For instance, represent known oncogenic drivers (such as EGFR non-small cell lung cancer), contribute hallmarks VEGFR pro-tumor angiogenesis), mediate resistance therapeutics hormones Insulin diabetes). Classically, transduce signals through various modes ligand-induced receptor dimerization subsequent kinase-mediated signaling; however, ~10% all metazoan pseudokinases—that is, they lack capability catalyze phosphotransfer. Our objective is ascertain how RTK pseudokinases relay extracellular cues without kinase activity whether can be targeted therapeutically. Using structural, biophysical, signaling approaches, we investigated this class shed light on potential non-catalytic mechanisms. We identified structural elements conserved between their relatives, found pseudokinase domains conformationally dynamic, uncovered a putative route drugging these receptors via “conformational disrupting” small molecules. findings suggest that could serve viable drug targets set scene for future dissection pathways have long been considered enigmatic.