A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor
A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor
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DOI：
10.1016/j.str.2008.05.001
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发表时间：
2008-06-01
期刊：
影响因子：
5.7
通讯作者：
Stevens, Raymond C.
中科院分区：
文献类型：
--
作者：
Hanson, Michael A.;Cherezov, Vadim;Stevens, Raymond C.
胆固醇在真核生物膜蛋白功能中的作用主要归因于对膜流动性和曲率的影响。我们提出了2.8埃分辨率晶体结构的热稳定的人β(2)-肾上腺素能受体结合胆固醇和部分逆激动剂替莫洛尔。受体作为单体与每个受体结合的两个不同的胆固醇分子呈反平行结合，但不在包装界面中，因此表明在螺旋I、II、III和IV之间存在结构相关的胆固醇结合位点。使用等温变性的热稳定性分析证实胆固醇类似物显著增强了受体的稳定性。一个共识基序被定义为预测44%的人类A类受体的胆固醇结合，这表明特异性的甾醇结合对其他G蛋白偶联受体的结构和稳定性很重要，并且该位点可能为治疗发现提供靶标。
The role of cholesterol in eukaryotic membrane protein function has been attributed primarily to an influence on membrane fluidity and curvature. We present the 2.8 angstrom resolution crystal structure of a thermally stabilized human beta(2)-adrenergic receptor bound to cholesterol and the partial inverse agonist timolol. The receptors pack as monomers in an antiparallel association with two distinct cholesterol molecules bound per receptor, but not in the packing interface, thereby indicating a structurally relevant cholesterol-binding site between helices I, II, III, and IV. Thermal stability analysis using isothermal denaturation confirms that a cholesterol analog significantly enhances the stability of the receptor. A consensus motif is defined that predicts cholesterol binding for 44% of human class A receptors, suggesting that specific sterol binding is important to the structure and stability of other G protein-coupled receptors, and that this site may provide a target for therapeutic discovery.