题名：Structure of the catalytic domain of the hepatitis C virus NS2-3 protease.
作者：Lorenz IC, Marcotrigiano J, Dentzer TG, Rice CM
来源：Nature 2006 Jul 23 [abstract on PubMed] ,Nature. 2006 Aug 17;442(7104):831-5.
摘要：Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Hepatitis C virus is a major global health problem affecting an estimated 170 million people worldwide. Chronic infection is common and can lead to cirrhosis and liver cancer. There is no vaccine available and current therapies have met with limited success. The viral RNA genome encodes a polyprotein that includes two proteases essential for virus replication. The NS2-3 protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A protease cleaves at four downstream sites in the polyprotein. NS3-4A is characterized as a serine protease with a chymotrypsin-like fold, but the enzymatic mechanism of the NS2-3 protease remains unresolved. Here we report the crystal structure of the catalytic domain of the NS2-3 protease at 2.3 A resolution. The structure reveals a dimeric cysteine protease with two composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer, and the nucleophilic cysteine by the other. The carboxy-terminal residues remain coordinated in the two active sites, predicting an inactive post-cleavage form. Proteolysis through formation of a composite active site occurs in the context of the viral polyprotein expressed in mammalian cells. These features offer unexpected insights into polyprotein processing by hepatitis C virus and new opportunities for antiviral drug design.
Selected by | Liang Tong / Patricia C. Weber / Robert Lanford / Peter Artymiuk / Robert Booth / Daniel Lamarre
First evaluation 8 Aug 2006 | Latest evaluation 30 Aug 2006
Columbia University, United States of America
This paper reports that the NS2-3 protease of hepatitis C virus is a cysteine protease with a novel fold, and that the active site is located at the interface of a dimer. The results suggest that dimerization (or NS2 concentration) may be a regulatory mechanism in the auto-processing of the viral polyprotein. NS2-3 carries out only one proteolysis reaction for the processing of viral polyproteins. The C-terminus of NS2 is located in the active site, blocking NS2 from acting on other substrates.
Evaluated 30 Aug 2006
Patricia C. Weber
Imiplex, United States of America
In an unexpected finding, the crystal structure of hepatitis C virus (HCV) NS2 cysteine protease revealed a novel protease oligomer with symmetric catalytic sites composed of residues from each chain of the dimer. Like HCV NS3 serine protease, the C-terminus of the mature NS2 protease occupies the enzyme active site and provides a second example of autoinhibition by an HCV-encoded protease. The disposition of neutral and hydrophobic residues suggests orientation of the NS2 active sites away from the membrane.
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