Billion-years old proteins show the importance of N-lobe orientation in Imatinib-kinase selectivity

The molecular origins of proteins' functions are a combinatorial search problem in the proteins' sequence space, which requires enormous resources to solve. However, evolution has already solved this optimization problem for us, leaving behind suboptimal solutions along the way. Comparing suboptimal proteins along the evolutionary pathway, or ancestors, with more optimal modern proteins can lead us to the exact molecular origins of a particular function. In this paper, we study the long-standing question of the selectivity of Imatinib, an anti-cancer kinase inhibitor drug. We study two related kinases, Src and Abl, and four of their common ancestors, to which Imatinib has significantly different affinities. Our results show that the orientation of the N-lobe with respect to the C-lobe varies between the kinases along their evolutionary pathway and is consistent with Imatinib's inhibition constants as measured experimentally. The conformation of the DFG-motif (Asp-Phe-Gly) and the structure of the P-loop also seem to have different stable conformations along the evolutionary pathway, which is aligned with Imatinib's affinity.