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首页> 外文期刊>Journal of Molecular Biology >Influence of Cholesterol and Its Stereoisomers on Members of the Serotonin Receptor Family
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Influence of Cholesterol and Its Stereoisomers on Members of the Serotonin Receptor Family

机译：胆固醇及其立体异构体对血清素受体家族成员的影响

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Despite the ubiquity of cholesterol within the cell membrane, the mechanism by which it influences embedded proteins remains elusive. Numerous G-protein coupled receptors exhibit dramatic responses to membrane cholesterol with regard to the ligand-binding affinity and functional properties, including the 5-HT receptor family. Here, we use over 25 mu s of unbiased atomistic molecular dynamics simulations to identify cholesterol interaction sites in the 5-HT1B and 5-HT2B receptors and evaluate their impact on receptor structure. Susceptibility to membrane cholesterol is shown to be subtype dependent and determined by the quality of interactions between the extracellular loops. Charged residues are essential for maintaining the arrangement of the extracellular surface in 5-HT2B; in the absence of such interactions, the extracellular surface of the 5-HT1B is malleable, populating a number of distinct conformations. Elevated cholesterol density near transmembrane helix 4 is considered to be conducive to the conformation of extracellular loop 2. Occupation of this site is also shown to be stereospecific, illustrated by differential behavior of nat-cholesterol isomers, ent- and epi-cholesterol. In simulations containing the endogenous agonist, serotonin, cholesterol binding at transmembrane helix 4 biases bound serotonin molecules toward an unexpected binding mode in the extended binding pocket. The results highlight the capability of membrane cholesterol to influence the mobility of the extracellular surface in the 5-HT1 receptor family and manipulate the architecture of the extracellular ligand-binding pocket. (C) 2019 Elsevier Ltd. All rights reserved.
机译：尽管细胞膜内胆固醇浓郁，但它影响嵌入蛋白质的机制仍然是难以捉摸的。许多G蛋白偶联受体对膜胆固醇具有显着的反应，关于配体结合亲和力和功能性质，包括5-HT受体家族。在这里，我们使用超过25μm的非偏见原子分子动力学模拟，以鉴定5-HT1B和5-HT2B受体中的胆固醇相互作用位点，并评估它们对受体结构的影响。对膜胆固醇的敏感性显示为亚型依赖性，通过细胞外环之间的相互作用质量确定。带电残余物对于维持5-HT2B中的细胞外表面的布置是必不可少的;在没有这种相互作用的情况下，5-HT1B的细胞外表面是可展望的，填充许多不同的构象。在跨膜螺旋4附近升高的胆固醇密度被认为是有利于细胞外环的构成2.占据该部位的职位也显示为立体特异性，通过NaT-胆固醇异构体，eNT-和外延胆固醇的差异行为所示。在含有内源性激动剂，血清素的模拟中，跨膜螺旋4的胆固醇结合4偏向于延伸的装订口中的意外结合模式的结合的血清素分子。结果突出了膜胆固醇对影响5-HT1受体家族中细胞外表面的迁移率的能力，并操纵细胞外配体结合口袋的结构。 （c）2019 Elsevier Ltd.保留所有权利。

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