Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites
Dynamic Profiling of β-Coronavirus 3CL Mpro Protease Ligand-Binding Sites
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DOI：
10.1021/acs.jcim.1c00449
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发表时间：
2021-06-14
影响因子：
5.6
通讯作者：
Haider, Shozeb
中科院分区：
文献类型：
--
作者：
Cho, Eunice;Rosa, Margarida;Haider, Shozeb
仅β-冠状病毒（CoV）一项就造成了21世纪世纪的三次重大全球疫情。目前的危机导致迫切需要开发治疗方法。尽管有许多疫苗可供使用，但仍需要针对基本病毒成分的替代策略，作为防止致命病毒变异出现的后备措施。一个这样的靶标是在病毒复制中起着不可或缺的作用的主要蛋白酶（M-pro）。超过270个M-pro X射线结构与抑制剂的复合物的可用性为配体-蛋白质相互作用提供了独特的见解。在此，我们提供了一个全面的比较，所有非冗余的配体结合位点的SARS-CoV 2，SARS-CoV，MERS-CoV M-pro。广泛的自适应采样已被用于使用马尔可夫状态模型（MSM）研究配体结合位点的结构保守性，并使用基于卷积变分自动编码器的深度学习比较构象动力学。我们的研究结果表明，尽管在β-CoV同源物中具有较高的序列和结构保守性，但并非所有的配体结合位点都是动态保守的。这突出了用单一pan抑制剂靶向所有三种M-pro酶的复杂性。
beta-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (M-pro) that plays an indispensable role in viral replication. The availability of over 270 M-pro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV M-pro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across beta-CoV homologs. This highlights the complexity in targeting all three M-pro enzymes with a single pan inhibitor.