Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34.
Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34.
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DOI：
10.1126/science.1184429
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发表时间：
2010-03-26
期刊：
影响因子：
--
通讯作者：
Williams RL
中科院分区：
文献类型：
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作者：
Miller S;Tavshanjian B;Oleksy A;Perisic O;Houseman BT;Shokat KM;Williams RL
磷脂酰肌醇3-激酶(PI3K)在健康和疾病中具有广泛而深刻的作用。原始的PI3K，Vps34，存在于所有真核生物中，在自噬、内体分选、吞噬和mTOR上游的信号传递中起着重要的作用。Vps34的晶体结构揭示了一个狭窄的腺嘌呤结合口袋，揭示了为什么这类PI3K的特定抑制剂被证明是难以捉摸的。Vps34的磷脂酰肌醇结合环和C末端螺旋都有双重作用：它们对膜上的催化是必不可少的，并且它们抑制无效的ATPase循环。Vps34似乎在细胞质中的闭合形式和膜上的开放形式之间交替。Vps34与一系列抑制剂的复合体结构揭示了自噬抑制剂3-甲基腺嘌呤优先抑制Vps34的原因，并为产生新的有效和特异的Vps34抑制剂奠定了基础。
Phosphoinositide 3-kinases (PI3Ks) have diverse and profound roles in health and disease. The primordial PI3K, Vps34, is present in all eukaryotes and has essential roles in autophagy, endosomal sorting, phagocytosis and signalling upstream of mTOR in nutrient sensing. The crystal structure of Vps34 reveals a constricted adenine-binding pocket, shedding light on why specific inhibitors of this class of PI3K have proven elusive. Both the phosphoinositide-binding loop and the C-terminal helix of Vps34 have dual roles: they are essential for catalysis on membranes and they suppress futile ATPase cycles. Vps34 appears to alternate between a closed form in the cytosol and an open form on the membrane. Structures of Vps34 complexes with a series of inhibitors show why the autophagy inhibitor 3-methyladenine preferentially inhibits Vps34 and lay a foundation for generating new potent and specific Vps34 inhibitors.