A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with SHIP2 Provides a Rationale for Drug Discovery

详细信息    查看全文

• 作者：Stephen J. Mills ; Camilla Persson ; Gyles Cozier ; Mark P. Thomas ; Lionel Tr茅saugues ; Christophe Erneux ; Andrew M. Riley ; P盲r Nordlund ; Barry V. L. Potter
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：May 18, 2012
• 年：2012
• 卷：7
• 期：5
• 页码：822-828
• 全文大小：417K
• 年卷期：v.7,no.5(May 18, 2012)
• ISSN：1554-8937

文摘

Phosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is thought to be involved in type-2 diabetes and obesity, conditions that could therefore be open to pharmacological modulation of the enzyme. However, rational design of SHIP2 inhibitors has been limited by the absence of a high-resolution structure. Here, we present a 2.1 脜 resolution crystal structure of the phosphatase domain of SHIP2 bound to the synthetic ligand biphenyl 2,3鈥?4,5鈥?6-pentakisphosphate (BiPh(2,3鈥?4,5鈥?6)P₅). BiPh(2,3鈥?4,5鈥?6)P₅ is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P₄ hydrolysis with an IC₅₀ of 24.8 卤 3.0 渭M, (K_m for Ins(1,3,4,5)P₄ is 215 卤 28 渭M). Molecular dynamics simulations suggest that when BiPh(2,3鈥?4,5鈥?6)P₅ binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs.