Structural Basis of Inhibition Specificities of 3C and 3C-like Proteases by Zinc-coordinating and Peptidomimetic Compounds
Resource
Journal of Biological Chemistry 284 (12): 7646-7655
Journal
Journal of Biological Chemistry
Pages
7646-7655
Date Issued
2009
Date
2009
Author(s)
Lee, Cheng-Chung
Kuo, Chih-Jung
Ko, Tzu-Ping
Hsu, Min-Feng
Tsui, Yao-Chen
Chang, Shih-Cheng
Yang, Syaulan
Chen, Shu-Jen
Chen, Hua-Chien
Hsu, Ming-Chu
Shih, Shin-Ru
Liang, Po-Huang
Wang, Andrew H.-J.
Abstract
Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3C(pro)) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CL(pro)) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CL(pro). As shown in the present study, some of these compounds were also found to be active against 3C(pro) of CV strain B3 (CVB3). Several crystal structures of 3C(pro) from CVB3 and 3CL(pro) from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His(40)-Cys(147) catalytic dyad of CVB3 3C(pro). The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies.
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