分类： 生物学 >> 病毒学 提交时间： 2020-03-06
摘要： 冠状病毒SARS-CoV，MERS-CoV和新发现的2019-nCoV所引发的传染性疾病严重威胁着人类的生命健康安全。位于冠状病毒表面的spike（S）糖蛋白在病毒传播及感染过程中负责结合宿主细胞受体，融合细胞中的膜结构等关键步骤，是病毒重要的药物靶点。其中在冠状病毒中高度保守的S2亚基作为融膜机器，介导了病毒与宿主之间的膜融合过程。我们运用冷冻电镜单颗粒三维重构技术解析了SARS-CoV S糖蛋白的融膜后构象的结构，展示了S2亚基在融膜过程中的结构特点和构象变化。结合保守性比对和糖基化修饰指认，这项工作分析了位于S2亚基的潜在药物靶点，有益于相关疫苗和药物的开发和设计。
分类： 生物学 >> 生物物理学 >> 细胞生物学 提交时间： 2016-05-12
Cao, Duanfang
Wang, Mingzhu
Yang, Na
Xu, Rui-Ming
Cao, Duanfang
Xu, Rui-Ming
Qiu, Xiayang
Liu, Dongxiang
Jiang, Hualiang
摘要： Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators.
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