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

被引：246

作者：

Miller, Simon ^{[1
]}

Tavshanjian, Brandon ^{[2
,3
]}

Oleksy, Arkadiusz ^{[1
]}

Perisic, Olga ^{[1
]}

Houseman, Benjamin T. ^{[2
,3
]}

Shokat, Kevan M. ^{[2
,3
]}

Williams, Roger L. ^{[1
]}

机构：

[1] MRC, Mol Biol Lab, Cambridge CB2 0QH, England

[2] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

来源：

SCIENCE | 2010年 / 327卷 / 5973期

关键词：

PHOSPHATIDYLINOSITOL 3-KINASE COMPLEXES; PHOSPHOINOSITIDE; 3-KINASE; SACCHAROMYCES-CEREVISIAE; REGULATES AUTOPHAGY; PROTEIN-KINASE; BECLIN; UVRAG; ACTIVATION; ENDOSOME; HVPS34;

D O I：

10.1126/science.1184429

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1638 / 1642

页数：5

共 27 条

[1] Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum [J].