eLIFE doi:10.7554/eLife.01998

Glycogen synthase kinase-3 (GSK3) is a constitutively active kinase that regulates diverse processes such as glucose homeostasis and development. Activation of insulin or Wnt/β-catenin signaling results in the inhibition of GSK3 activity through distinct mechanisms: insulin signaling turns on Akt expression, which phosphorylates GSK3 at a serine near the N terminus to generate an autoinhibitory peptide that blocks substrate access. In contrast, several models suggest that Wnt signaling promotes GSK3 inhibition by translocating GSK3 to the membrane, where it directly interacts with the phosphorylated co-receptor LRP5/6. To examine the effects of GSK3 inhibition on protein conformation, Stamos et al. obtained the crystal structure of GSK3 bound to the N-terminal phosphorylated peptide or phosphorylated LRP6 motifs. The authors found that these inhibitory peptides occupied the substrate binding pocket, acting as pseudo-substrates that promote conformational changes in the 'C-loop' and the glycine-rich N-terminal loop, indicative of a catalytically active structure. The C-loop rearrangement resulted in direct interactions with the inhibitory peptides. Finally, the authors identified residues on both GSK3 (Phe93) and on the inhibitor peptide (positions 2 and 5 after the phosphorylation site) that mediate substrate binding. Overall, these structural observations provide useful insight that will inform future development of specific GSK3 inhibitors.