MAPPING OF GENERAL ANESTHETIC TARGET SITES PROVIDES A MOLECULAR-BASIS FOR CUTOFF EFFECTS
MAPPING OF GENERAL ANESTHETIC TARGET SITES PROVIDES A MOLECULAR-BASIS FOR CUTOFF EFFECTS
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DOI：
10.1038/316349a0
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发表时间：
1985-01-01
期刊：
影响因子：
64.8
通讯作者：
LIEB, WR
中科院分区：
文献类型：
--
作者：
FRANKS, NP;LIEB, WR
全身麻醉中一个长期存在且尚未解决的问题是所谓的“截止”效应;当一个人提升一系列同源的麻醉剂时，麻醉剂的效力随着麻醉剂的大小而逐渐增加，但随后，麻醉剂的效力突然消失1 -5。奇怪的是，这种效力的截止发生在不同系列的非常不同的点上。已经提供了各种解释5，6，通常基于脂质双层是全身麻醉的主要靶点的概念3，4，7。然而，越来越多的证据表明，蛋白质是主要的作用位点8 -14。在这里，我们展示了麻醉抑制的可溶性蛋白质（萤火虫荧光素酶），这反映了那些发现全身麻醉的截止效应，我们描述了如何结合位点的分子结构占不同的截断在不同的同源系列。我们表明，这种行为是一个自然的结果，麻醉剂绑定到一个两亲性蛋白口袋的限制尺寸。当使用效能数据的精细细节绘制出动物和荧光素酶蛋白的全身麻醉靶位点时，揭示了显着的相似性。因此，我们的结果表明全身麻醉中的目标位点是蛋白质上的两亲性口袋。
A longstanding and unresolved problem in general anaesthesia is the so-called ‘cutoff’ effect; as one ascends a homologous series of anaesthetic agents, the potencies progressively increase with anaesthetic size but then, rather suddenly, anaesthetic potency disappears1–5. Curiously, this cutoff in potency occurs at very different points in different series. Various explanations have been offered5,6, usually based on the notion that lipid bilayers are the primary target sites in general anaesthesia3,4,7. However, accumulating evidence now suggests that proteins are the primary sites of action8–14. Here we demonstrate cutoff effects for the anaesthetic inhibition of a soluble protein (firefly luciferase) which mirror those found for general anaesthesia, and we describe how the molecular architecture of the binding site accounts for the different cutoffs in the different homologous series. We show that this behaviour is a natural consequence of anaesthetics binding to an amphiphilic protein pocket of circumscribed dimensions. When general anaesthetic target sites in animals and the luciferase protein are mapped out using the fine details of the potency data, remarkable similarities are revealed. Our results thus suggest that the target sites in general anaesthesia are amphiphilic pockets on proteins.