Analysis of the effect of mutations on the response to Hsp90 inhibition. a) Kinases with a mutation detected by next generation sequencing. Shown are the differences in the response to geldanamycin. For each kinase the non-mutated cell line most weakly responding was used as a reference for comparison with the response in the other cell lines. Kinase names printed in bold are known or newly identified candidate clients of Hsp90. b) Superposition of the kinase domains of ErbB1/EGFR (yellow), and RIPK2 (blue) shows structural conservation. c) Potential mechanism for the differential response of RIPK2 to geldanamycin. Overview of kinase domain (left), close-up of affected region in wild type (middle) and mutant (right) protein. In wild type RIPK2 R123 (red) interacts with Tyr77 of the putative Hsp90 recognition loop (green) (left, middle panel). In the R123H mutant this interaction is lost (right panel).