Binding of the general anesthetics propofol and halothane to human serum albumin - High resolution crystal structures
Binding of the general anesthetics propofol and halothane to human serum albumin - High resolution crystal structures
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DOI：
10.1074/jbc.m005460200
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发表时间：
2000-12-08
影响因子：
4.8
通讯作者：
Franks, NP
中科院分区：
文献类型：
--
作者：
Bhattacharya, AA;Curry, S;Franks, NP
人血清白蛋白（HSA）是循环系统中最丰富的蛋白质之一，在脂肪酸，代谢产物和药物的运输中起关键作用。对于许多药物，与血清白蛋白结合是其分布和药代动力学的关键决定因素。但是，目前尚无针对药物 - 珠蛋白复合物发表的高分辨率晶体结构。在这里，我们描述了HSA的高分辨率晶体结构，其中两种最广泛使用的一般麻醉剂，丙泊酚和硫烷。此外，我们描述了与硫烷和脂肪酸复合的HSA的晶体结构。我们表明，静脉麻醉丙泊酚在已显示可容纳脂肪酸的预制口袋的HSA上的两个离散位点上结合。同样，我们表明，在三个位点也是脂肪酸结合基因座的三个位点，吸入剂卤烷硫烷结合（在药理学相关范围内的浓度下）。在更高的氟烷浓度下，我们已经确定了所占据的其他位点，所有较高的亲和力麻醉结合位点本质上都是两亲性的，具有极性和脂肪性部分，并且麻醉结合仅会导致局部结构的较小变化。
Human serum albumin (HSA) is one of the most abundant proteins in the circulatory system and plays a key role in the transport of fatty acids, metabolites, and drugs. For many drugs, binding to serum albumin is a critical determinant of their distribution and pharmacokinetics; however, there have as yet been no high resolution crystal structures published of drug-albumin complexes. Here we describe high resolution crystal structures of HSA with two of the most widely used general anesthetics, propofol and halothane. In addition, we describe a crystal structure of HSA complexed with both halothane and the fatty acid, myristate. We show that the intravenous anesthetic propofol binds at two discrete sites on HSA in preformed pockets that have been shown to accommodate fatty acids. Similarly we show that the inhalational agent halothane binds (at concentrations in the pharmacologically relevant range) at three sites that are also fatty acid binding loci. At much higher halothane concentrations, we have identified additional sites that are occupied, All of the higher affinity anesthetic binding sites are amphiphilic in nature, with both polar and apolar parts, and anesthetic binding causes only minor changes in local structure.