Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34

Abstract

Lipid Kinase Revealed The lipid kinase, Vps34, makes the key signaling lipid phosphatidylinositol 3-phosphate [PI(3)P] and has essential roles in autophagy, membrane trafficking, and cell signaling. It is a class III PI 3-kinase, a class against which there is currently no specific inhibitor. Miller et al. (p. 1638 ) now describe the crystal structure of Vps34. Modeling substrate binding and combining structural data with mutagenesis suggests a mechanism in which Vps34 is auto-inhibited in solution, but adopts a catalytically active conformation on membranes. Structures of Vps34 with existing inhibitors might allow for the generation of inhibitors with high affinity and specificity.