2X6K

THE CRYSTAL STRUCTURE OF THE DROSOPHILA CLASS III PI3-KINASE VPS34 IN COMPLEX WITH PI-103

Summary for 2X6K

• Entry DOI: 10.2210/pdb2x6k/pdb
• Related: 2X6F 2X6H 2X6I 2X6J
• Descriptor: PHOSPHOTIDYLINOSITOL 3 KINASE 59F, SULFATE ION, 3-(4-MORPHOLIN-4-YLPYRIDO[3',2':4,5]FURO[3,2-D]PYRIMIDIN-2-YL)PHENOL (3 entities in total)
• Functional Keywords: pi103, pi-103, autophagy, transferase, pi3k class iii, phosphoinositide 3-kinase class iii
• Biological source: DROSOPHILA MELANOGASTER (FRUIT FLY)
• Total number of polymer chains: 2
• Total formula weight: 158515.84

Authors

Miller, S.,Tavshanjian, B.,Oleksy, A.,Perisic, O.,Houseman, B.T.,Shokat, K.M.,Williams, R.L. (deposition date: 2010-02-17, release date: 2010-04-07, Last modification date: 2023-12-20)

Primary citation

Miller, S.,Tavshanjian, B.,Oleksy, A.,Perisic, O.,Houseman, B.T.,Shokat, K.M.,Williams, R.L.
Shaping Development of Autophagy Inhibitors with the Structure of the Lipid Kinase Vps34.
Science, 327:1638-, 2010

PubMed Abstract: Phosphoinositide 3-kinases (PI3Ks) are lipid kinases with diverse roles in health and disease. The primordial PI3K, Vps34, is present in all eukaryotes and has essential roles in autophagy, membrane trafficking, and cell signaling. We solved the crystal structure of Vps34 at 2.9 angstrom resolution, which revealed a constricted adenine-binding pocket, suggesting the reason that specific inhibitors of this class of PI3K have proven elusive. Both the phosphoinositide-binding loop and the carboxyl-terminal helix of Vps34 mediate catalysis on membranes and suppress futile adenosine triphosphatase cycles. Vps34 appears to alternate between a closed cytosolic form and an open form on the membrane. Structures of Vps34 complexes with a series of inhibitors reveal the reason that an autophagy inhibitor preferentially inhibits Vps34 and underpin the development of new potent and specific Vps34 inhibitors.

PubMed: 20339072
DOI: 10.1126/SCIENCE.1184429

Experimental method

X-RAY DIFFRACTION (3.5 Å)