Photo: Jonne Renvall

Together with our collaborators, S. Knapp group (SGC/Frankfurt) and M. Lemmon group (Yale University), we worked to understand how Wnt-receptor pseudokinases function, by combining crystallographic, biophysical and chemical biology studies (Sheetz JB et al., Mol Cell, 2020). We show that their pseudokinase domains adopt structures closely related to the inactive state of their closest kinase-active homologue, insulin receptor. We also identified that ROR1 pseudokinase domain devoid of ATP binding can still be targeted with small molecules (such as ponatinib) that bind to its vestigial ATP-binding site in a highly specific manner and induce conformational changes that mimic signaling regulation. Our study pioneered the way we understand signaling by Wnt-related receptor pseudokinases, opening new avenues to make use of these proteins as therapeutic targets.