Figure 5.

Elucidation of novel GSK3α crystal structures; (A) crystal structure of GSK3α with the small molecule inhibitor BRD0705. The compound interacts with the hinge through three hydrogen bonds (indicated with red dashed lines). (B) Overlay of BRD0705 bound with GSK3α and GSK3β shows similar hinge interactions; however, there are sidechain rotamer differences that lead to subtle differences in the binding pocket in Figure 5B vs Figure 5A. (C) Asp vs Glu difference between GSK3α and GSK3β leads to differences in hydrogen bonding interactions behind the binding pocket. (D) Addition of a trifluoromethyl group to the phenyl ring may lead to increased affinity of these compounds for either GSK3 paralog by enhancing hydrogen bonding interactions between the Fluoro group and Lys 85/148.