Dynamic Profiling of ?-Coronavirus 3CL Mpro Protease Ligand-Binding Sites [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 574.87 [Unassigned]
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2021
• Mô tả vật lý: Size: p. 3058-3073 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 259670
• Chủ đề: 1. 59 basic biological sciences; 2. 60 applied life sciences; 3. Conformation; 4. Ligands; 5. Peptides and proteins; 6. Sars-cov; 7. Screening assays

Tóm tắt

?-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 (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro 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 Mpro. 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 ?-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.