Editors' ChoiceStructural Biology

Lipid Kinase Revealed

Science Signaling  30 Mar 2010:
Vol. 3, Issue 115, pp. ec99
DOI: 10.1126/scisignal.3115ec99

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. 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.

S. Miller, B. Tavshanjian, A. Oleksy, O. Perisic, B. T. Houseman, K. M. Shokat, R.L. Williams, Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 327, 1638–1642 (2010). [Abstract] [Full Text]