Chen Yun, Guo Yao, Pan Yihang, Zhao Zhizhuang Joe
Edmond H. Fischer Translational Medical Research Laboratory, Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
Edmond H. Fischer Translational Medical Research Laboratory, Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
Biochem Biophys Res Commun. 2020 Feb 17;525(1):135-40. doi: 10.1016/j.bbrc.2020.02.071.
2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.
2019新型冠状病毒是一种新发现的冠状病毒，与严重急性呼吸综合征冠状病毒（SARS-CoV）高度相似。我们对负责冠状病毒进入宿主细胞的刺突糖蛋白的受体结合域（RBD）进行了结构分析。两种病毒的RBD在氨基酸序列上有72%的同一性，分子模拟显示它们的三元结构高度相似。然而，2019新型冠状病毒有一个独特的环，其中柔性的甘氨酰残基取代了SARS-CoV中刚性的脯氨酰残基。分子建模显示，2019新型冠状病毒RBD与血管紧张素转换酶2（ACE2）有更强的相互作用。柔性环中一个独特的苯丙氨酸F486可能起主要作用，因为它插入了ACE2中的一个深疏水口袋。ACE2在从鱼类、两栖动物、爬行动物、鸟类到哺乳动物的整个动物界中广泛表达，其一级结构保守。结构分析表明，这些动物的ACE2可能潜在地结合2019新型冠状病毒的RBD，使它们都可能成为该病毒的天然宿主。2019新型冠状病毒被认为是通过呼吸道飞沫传播的。然而，由于ACE2主要在肠道、睾丸和肾脏中表达，粪口传播和其他传播途径也有可能。最后，应开发能够阻断ACE2与RBD相互作用的抗体和小分子抑制剂来对抗该病毒。
