Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad 500032, India.
IHub-Data, International Institute of Information Technology, Hyderabad 500032, India.
J Phys Chem B. 2023 Nov 9;127(44):9476-9495. doi: 10.1021/acs.jpcb.3c02255. Epub 2023 Oct 25.
The smoothened (SMO) receptor belongs to the superfamily of class F G protein-coupled receptors (GPCRs) and is a potential drug target in several types of cancer. It has two ligand binding sites, respectively, in the cysteine-rich domain (CRD) and the transmembrane domain (TMD). It has been shown that cholesterol is important for its activation and function. However, the molecular-level understanding of SMO dynamics in the presence of cholesterol has not been explored in sufficient detail. In this work, we have carried out atomistic molecular dynamics simulations totaling 3.6 μs to analyze the effect of cholesterol binding to TMD and/or CRD on the structure and dynamics of the SMO receptor. Our results show that the presence of cholesterol in the CRD and TMD, respectively, alters the conformational dynamics of SMO differently. We reported that the reorganization of the D-R-E network at the extracellular end of the TMD is important for the high activity of SMO. In general, the transmembrane helices 5, 6, and 7 and helix 8 are most affected, which, in turn, leads to changes in the CRD and intracellular cytoplasmic domain (ICD) dynamics patterns depending on the presence or absence of cholesterol in the CRD and/or the TMD. We have also reported that the interaction of membrane lipids with SMO is different in different SMO states. These results agree with the experimental structural observations and data of cholesterol-bound and unbound structures of SMO and add to our molecular understanding of the SMO-cholesterol interaction.
smoothened (SMO) 受体属于 F 类 G 蛋白偶联受体 (GPCR) 超家族，是几种类型癌症的潜在药物靶点。它在富含半胱氨酸的结构域 (CRD) 和跨膜结构域 (TMD) 中分别有两个配体结合位点。已经表明胆固醇对于其激活和功能很重要。然而，在胆固醇存在的情况下，SMO 动力学的分子水平理解还没有得到充分的探索。在这项工作中，我们进行了总计 3.6 μs 的原子分子动力学模拟，以分析胆固醇结合到 TMD 和/或 CRD 对 SMO 受体结构和动力学的影响。我们的结果表明，胆固醇分别存在于 CRD 和 TMD 中，会以不同的方式改变 SMO 的构象动力学。我们报告说，TMD 细胞外端的 D-R-E 网络的重排对于 SMO 的高活性很重要。一般来说，跨膜螺旋 5、6 和 7 以及螺旋 8 受影响最大，这反过来又会导致 CRD 和细胞内胞质域 (ICD) 动力学模式的变化，具体取决于 CRD 和/或 TMD 中是否存在胆固醇。我们还报告说，膜脂与 SMO 的相互作用在不同的 SMO 状态下是不同的。这些结果与实验结构观察和 SMO 结合和未结合结构的胆固醇数据一致，并为我们对 SMO-胆固醇相互作用的分子理解增添了新的内容。
