Structural Analysis of Coxsackievirus B3 3C Protease and its Inhinitor Complex: Implications in Antiviral Drug Design
Date Issued
2005
Date
2005
Author(s)
Tsui, Yao-Chen
DOI
en-US
Abstract
Coxsackievirus B3 (CVB3) causes acute or chronic myocarditis, which may lead to death, especially in children. Until now, there is no specific therapy for CVB3 other than treatment to relieve pain and other symptoms. CVB3 3C protease (3Cpro), a member of the picornaviridae cysteine protease, is required to cleave the viral polyprotein into functional proteins. CVB3 3Cpro is highly conserved in different strains and essential for viral maturation and infectivity, making it an attractive target for the development of antiviral drugs. Here we report the first crystal structures of native CVB3 3Cpro and its mutant (C147A) at 1.8 Å and 1.4 Å resolution, espectively. The structure of CVB3 3Cpro adopts a chymotrypsin-like fold and possesses a catalytic triad, Cys-His-Glu, which is
similar to the configuration of the Ser-His-Asp triad in almost all serine proteases. Furthermore, we analyzed the inhibition activity of CVB3 3Cpro with several SARS 3C-like protease inhibitors and determined a structure of co-crystallized proteaseinhibitor complex at 1.7 Å resolution. The inhibitor, TG4998, interacts with CVB3 3Cpro through a covalent bond with Cys147 of the catalytic triad and hydrogen bonds in the active-site pocket. The main effect on enzyme-inhibition depends upon the interactions between CVB3 3Cpro and the P1, P2 and P4 residues of TG4998. Collectively, these structural characteristics provide valuable basis for antiviral drug design.
Subjects
克沙奇
蛋白酶
抗病毒藥物
晶體結構
coxsackievirus
3C
protease
structure
antiviral drug
Type
other
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