Structure of GSK3 beta reveals a primed phosphorylation mechanism

GSK3 beta was identified as the kinase that phosphorylates glycogen synthas e but is now known to be involved in multiple signaling pathways. GSK3 beta prefers prior phosphorylation of its substrates. We present the structure of unphosphorylated GSK3 beta at 2.7 A. The orientation of the two domains and positioning of the activation loop of GSK3 beta are similar to those ob served in activated kinases. A phosphate ion held by Arg 96, Arg 180 and Ly s 205 occupies the same position as the phosphate group of the phosphothreo nine in activated p38 gamma, CDK2 or ERK2. A loop from a neighboring molecu le in the crystal occupies a portion of the substrate binding groove. The s tructure explains the unique primed phosphorylation mechanism of GSK3 beta and how GSK3 beta relies on a phosphoserine in the substrate for the alignm ent of the beta- and alpha -helical domains.