Insights on cross-species transmission of SARS-CoV-2 from structural modeling.
Insights on cross-species transmission of SARS-CoV-2 from structural modeling.
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DOI：
10.1371/journal.pcbi.1008449
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发表时间：
2020-12
影响因子：
4.3
通讯作者：
Levitt M
中科院分区：
文献类型：
--
作者：
Rodrigues JPGLM;Barrera-Vilarmau S;M C Teixeira J;Sorokina M;Seckel E;Kastritis PL;Levitt M
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是造成当前全球大流行的罪魁祸首，该疾病已感染全球 180 多个国家的超过 3100 万人。与其他冠状病毒一样，SARS-CoV-2被认为是从野生动物传播给人类的。鉴于当前大流行的规模和广泛的地理分布以及已确诊的跨物种传播病例，出现了这种传播可能的程度以及区分易感动物和非易感动物物种的分子特征的问题。在这里，我们研究了与 SARS-CoV-2 刺突蛋白结合的几种 ACE2 直向同源物的结构特性。我们发现已知不易受 SARS-CoV-2 感染的物种在几个 ACE2 氨基酸残基中存在非保守突变，这些突变破坏了与病毒刺突蛋白的关键极性和电荷接触。我们的模型还允许我们预测亲和力增强突变，这些突变可用于设计用于治疗目的的 ACE2 变体。最后，我们的研究为病毒-宿主蛋白相互作用建模提供了蓝图，并强调了设计这些计算研究和分析其结果时的几个重要考虑因素。 SARS-CoV-2 感染多种动物物种，包括人类。与许多其他病毒一样，其感染周期的第一步是病毒蛋白与宿主细胞膜上的受体蛋白之间的相互作用。在原子水平上表征此类蛋白质相互作用的三维结构对于了解感染过程、帮助开发针对感染的治疗方法以及预测哪些其他动物物种面临风险非常重要。在实验上，这种表征通常很困难、昂贵且不适用于大规模。在这里，我们表明计算模型可以填补一些空白，即提供一个结构框架来解释为什么人类容易受到 SARS-CoV-2 感染，而小鼠和鸡则不易感染。我们的模型还以合理的准确性绘制了宿主受体的关键氨基酸，这可以帮助指导抗病毒疗法的开发。我们的工作为使用计算模型研究病毒-宿主蛋白相互作用提供了蓝图，为实验提供了快速且廉价的补充，并有利于我们对病毒感染和药物开发的基本了解。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 31 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic and confirmed cases of cross-species transmission, the question of the extent to which this transmission is possible emerges, as well as what molecular features distinguish susceptible from non-susceptible animal species. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also allow us to predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results. SARS-CoV-2 infects multiple animal species, including humans. Like many other viruses, the first step in its infection cycle is the interaction between a viral protein and a receptor protein on the host cell membrane. Characterizing the three-dimensional structure of such protein interactions, at the atomic level, is very important to understand the infection process, to help develop therapeutics against it, and to predict which other animal species are at risk. Experimentally, this characterization is usually difficult, expensive, and not applicable on a large scale. Here, we show that computational modeling can fill in some of the gaps, namely provide a structural framework to explain why humans are susceptible to SARS-CoV-2 infection, while mice and chicken are not. Our models also map, with reasonable accuracy, key amino acids of the host receptor, which can help guide the development of antiviral therapeutics. Our work serves as a blueprint for studying viral-host protein interactions using computational modeling, providing a quick and inexpensive complement to experiments, and benefits both our basic understanding of viral infections and drug development.
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影响因子：
4.1
作者：
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影响因子：
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DOI：
10.1073/pnas.2010146117
发表时间：
2020-09-08
影响因子：
11.1
作者：
Damas, Joana;Hughes, Graham M;Lewin, Harris A
通讯作者：
Lewin, Harris A