Figure 2. Conservation at the drug targets.

The drug targets (here: the kinase domain of anaplastic lymphoma kinase, ALK) are usually proteins whose function is crucial to the tumor cells. Such proteins include many residues where modifications are limited or unlikely to be tolerated (conserved residues, see the color code). Even at less conserved residues, random mutations can lead to destabilization of the structure or interfere with the biological activity. Under strong selective pressure on the tumor due to drugs (here: crizotinib, represented with balls-and-sticks), some mutations can become beneficial and lead to improved fitness. Evolutionary conservation was calculated with Consurf [83]. Molecular graphics and analyses were performed with the UCSF Chimera package [84]. UCSF Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).