Identification of Two New Cholesterol Interaction Sites on the A2A Adenosine Receptor.
Identification of Two New Cholesterol Interaction Sites on the A2A Adenosine Receptor.
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DOI：
10.1016/j.bpj.2017.09.027
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发表时间：
2017-12
影响因子：
3.4
通讯作者：
Eric Rouvière;C. Arnarez;Lewen Yang;E. Lyman
中科院分区：
文献类型：
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作者：
Eric Rouvière;C. Arnarez;Lewen Yang;E. Lyman
按摩尔计算，胆固醇是动物细胞质膜中最丰富的成分。许多膜蛋白已被证明在功能上依赖于胆固醇，其中一些膜蛋白还被证明在其面向膜的表面上明确的位置结合胆固醇。在这项工作中，粗粒度“Martini”和全原子模拟的组合被用来识别 A2A 腺苷受体上的两个新的胆固醇结合位点，A2A 腺苷受体是一种 G 蛋白偶联受体，是帕金森病治疗的靶点。在该蛋白质的几个最近的高分辨率晶体结构中还观察到其中一个位点与胆固醇结合，并且在模拟中，仅当与反向激动剂 ZM241385 结合时才与胆固醇相互作用。对胆固醇结合位点进行编目是了解膜蛋白胆固醇依赖性功能的重要一步。鉴于质膜中的胆固醇含量随细胞类型和广泛使用的药物（如他汀类药物）的给药而变化，了解胆固醇依赖性功能是利用膜成分变化用于治疗目的的重要一步。
By mole, cholesterol is the most abundant component of animal cell plasma membranes. Many membrane proteins have been shown to be functionally dependent on cholesterol, several of which have also been shown to bind cholesterol at well-defined locations on their membrane-facing surface. In this work, a combination of coarse-grained "Martini" and all-atom simulations are used to identify two, to our knowledge, new cholesterol-binding sites on the A2Aadenosine receptor, a G-protein-coupled receptor that is a target for the treatment of Parkinson's disease. One of the sites is also observed to bind cholesterol in several recent, high-resolution crystal structures of the protein, and in the simulations, interacts with cholesterol only when bound to the inverse agonist ZM241385. Cataloguing cholesterol-binding sites is a vital step in the effort to understand cholesterol-dependent function of membrane proteins. Given that cholesterol content in plasma membranes varies with cell type and on administration of widely prescribed pharmaceuticals, such as statins, understanding cholesterol-dependent function is an important step toward exploiting membrane compositional variation for therapeutic purposes.