7EO7

Crystal structure of HCoV-NL63 3C-like protease in complex with an inhibitor Shikonin

7EO7 の概要

• エントリーDOI: 10.2210/pdb7eo7/pdb
• 分子名称: 3C-like proteinase, 2-[(1R)-4-methyl-1-oxidanyl-pent-3-enyl]-5,8-bis(oxidanyl)naphthalene-1,4-dione (3 entities in total)
• 機能のキーワード: hcov, viral protein
• 由来する生物種: Human coronavirus NL63 (HCoV-NL63)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65814.55

構造登録者

Gao, H.X.,Zhang, Y.T.,Zhou, X.L.,Zhong, F.L.,Li, J.,Zhang, J. (登録日: 2021-04-21, 公開日: 2021-10-20, 最終更新日: 2023-11-29)

主引用文献

Zhang, Y.,Gao, H.,Hu, X.,Wang, Q.,Zhong, F.,Zhou, X.,Lin, C.,Yang, Y.,Wei, J.,Du, W.,Huang, H.,Zhou, H.,He, W.,Zhang, H.,Zhang, Y.,McCormick, P.J.,Fu, J.,Wang, D.,Fu, Y.,Lu, X.,Zhang, T.,Duan, J.,Qin, B.,Jiang, H.,Luo, J.,Zhang, Y.,Chen, Q.,Luo, Q.,Cheng, L.,Zhang, Z.,Zhang, J.,Li, J.
Structure-Based Discovery and Structural Basis of a Novel Broad-Spectrum Natural Product against the Main Protease of Coronavirus.
J.Virol., 96:e0125321-e0125321, 2022

PubMed Abstract: Over the past 20 years, the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2 emerged, causing severe human respiratory diseases throughout the globe. Developing broad-spectrum drugs would be invaluable in responding to new, emerging coronaviruses and to address unmet urgent clinical needs. Main protease (M; also known as 3CL) has a major role in the coronavirus life cycle and is one of the most important targets for anti-coronavirus agents. We show that a natural product, noncovalent inhibitor, shikonin, is a pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, human coronavirus (HCoV)-HKU1, HCoV-NL63, and HCoV-229E with micromolar half maximal inhibitory concentration (IC) values. Structures of the main protease of different coronavirus genus, SARS-CoV from the betacoronavirus genus and HCoV-NL63 from the alphacoronavirus genus, were determined by X-ray crystallography and revealed that the inhibitor interacts with key active site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses as well as emerging coronaviruses of the future. Given the importance of the main protease for coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. The current pandemic has created an urgent need for broad-spectrum inhibitors of SARS-CoV-2. The main protease is relatively conservative compared to the spike protein and, thus, is one of the most promising targets in developing anti-coronavirus agents. We solved the crystal structures of the main protease of SARS-CoV and HCoV-NL63 that bound to shikonin. The structures provide important insights, have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad-spectrum anti-coronavirus ligands as new therapeutic agents.

PubMed: 34586857
DOI: 10.1128/JVI.01253-21

実験手法

X-RAY DIFFRACTION (2.24916621935 Å)