Sengupta Durba, Chattopadhyay Amitabha
CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Biochim Biophys Acta. 2015 Sep;1848(9):1775-82. doi: 10.1016/j.bbamem.2015.03.018. Epub 2015 Mar 25.
G protein-coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across cell membranes and represent major targets in the development of novel drug candidates. Membrane cholesterol plays an important role in GPCR structure and function. Molecular dynamics simulations have been successful in exploring the effect of cholesterol on the receptor and a general consensus molecular view is emerging. We review here recent molecular dynamics studies at multiple resolutions highlighting the main features of cholesterol-GPCR interaction. Several cholesterol interaction sites have been identified on the receptor that are reminiscent of nonannular sites. These cholesterol hot-spots are highly dynamic and have a microsecond time scale of exchange with the bulk lipids. A few consensus sites (such as the CRAC site) have been identified that correspond to higher cholesterol interaction. Interestingly, high plasticity is observed in the modes of cholesterol interaction and several sites have been suggested to have high cholesterol occupancy. We therefore believe that these cholesterol hot-spots are indicative of 'high occupancy sites' rather than 'binding sites'. The results suggest that the energy landscape of cholesterol association with GPCRs corresponds to a series of shallow minima interconnected by low barriers. These specific interactions, along with general membrane effects, have been observed to modulate GPCR organization. Membrane cholesterol effects on receptor structure and organization, that in turn influences receptor cross-talk and drug efficacy, represent a new frontier in GPCR research. This article is part of a Special Issue entitled: Lipid-protein interactions. Guest Editors: Amitabha Chattopadhyay and Jean-Marie Ruysschaert.
G蛋白偶联受体（GPCRs）是参与跨细胞膜信号转导的最大一类分子，也是新型候选药物研发的主要靶点。膜胆固醇在GPCR的结构和功能中起着重要作用。分子动力学模拟已成功用于探索胆固醇对该受体的影响，一种普遍认可的分子观点正在形成。我们在此综述了近期在多个分辨率下进行的分子动力学研究，突出了胆固醇与GPCR相互作用的主要特征。在受体上已鉴定出几个类似于非环状位点的胆固醇相互作用位点。这些胆固醇热点具有高度动态性，与主体脂质的交换时间尺度为微秒级。已确定了一些一致性位点（如CRAC位点），它们对应着更高的胆固醇相互作用。有趣的是，在胆固醇相互作用模式中观察到高度可塑性，并且已提出几个位点具有高胆固醇占有率。因此，我们认为这些胆固醇热点指示的是“高占有率位点”而非“结合位点”。结果表明，胆固醇与GPCR结合的能量态势对应于一系列由低势垒相互连接的浅最小值。已观察到这些特定相互作用以及一般的膜效应会调节GPCR的组织。膜胆固醇对受体结构和组织的影响，进而影响受体间的相互作用和药物疗效，代表了GPCR研究的一个新前沿。本文是名为“脂质 - 蛋白质相互作用”特刊的一部分。客座编辑：阿米塔布·查托帕迪亚和让 - 玛丽·里斯沙尔特。
