CSIR-National Chemical Laboratory, Pune, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Adv Exp Med Biol. 2018;1112:151-160. doi: 10.1007/978-981-13-3065-0_11.
The interaction of G protein-coupled receptors (GPCRs) with cholesterol is a hallmark of their function, organization, and structural dynamics. Several cholesterol interaction sites, such as the cholesterol recognition amino acid consensus (CRAC) and cholesterol consensus motif (CCM), have been mapped from crystallography, bioinformatics, and simulation studies. In this article, we characterize common descriptors for cholesterol interaction sites in the serotonin receptor from a series of coarse-grain simulations. We have identified a novel interaction mode for cholesterol in which the cholesterol polar headgroup interacts with aromatic amino acid residues, such as tryptophan and tyrosine. The cholesterol rings interact with both aromatic residues and nonpolar residues, thereby constituting a signature aromatic interaction site. In addition, we report a similar binding mode in the crystal structures of the serotonin receptor, suggesting that this binding mode could be a general feature of the serotonin receptor family. Interestingly, this signature aromatic interaction site is present along with one of the CRAC motifs in the serotonin receptor. Our results represent an important step toward mapping out the diversity of cholesterol-GPCR interaction sites.
G 蛋白偶联受体（GPCRs）与胆固醇的相互作用是其功能、组织和结构动态的标志。已经通过晶体学、生物信息学和模拟研究映射出了几个胆固醇相互作用位点，例如胆固醇识别氨基酸共识（CRAC）和胆固醇共识基序（CCM）。在本文中，我们从一系列粗粒度模拟中对血清素受体中的胆固醇相互作用位点的常见描述符进行了表征。我们已经确定了胆固醇的一种新的相互作用模式，其中胆固醇极性头部基团与芳香族氨基酸残基（如色氨酸和酪氨酸）相互作用。胆固醇环与芳香族残基和非极性残基相互作用，从而构成了一个特征性的芳香族相互作用位点。此外，我们还在血清素受体的晶体结构中报告了类似的结合模式，表明这种结合模式可能是血清素受体家族的一个普遍特征。有趣的是，这个特征性的芳香族相互作用位点与血清素受体中的一个 CRAC 基序同时存在。我们的研究结果代表了在描绘胆固醇-GPCR 相互作用位点多样性方面迈出的重要一步。
