丙型肝炎病毒NS3蛋白酶结构域与合成NS4A辅助因子肽形成的复合物的晶体结构。

Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.

作者信息

Kim J L, Morgenstern K A, Lin C, Fox T, Dwyer M D, Landro J A, Chambers S P, Markland W, Lepre C A, O'Malley E T, Harbeson S L, Rice C M, Murcko M A, Caron P R, Thomson J A

机构信息

Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4242, USA.

出版信息

Cell. 1996 Oct 18;87(2):343-55. doi: 10.1016/s0092-8674(00)81351-3.

DOI:10.1016/s0092-8674(00)81351-3

PMID:8861917

Abstract

An estimated 1% of the global human population is infected by hepatitis C viruses (HCVs), and there are no broadly effective treatments for the debilitating progression of chronic hepatitis C. A serine protease located within the HCV NS3 protein processes the viral polyprotein at four specific sites and is considered essential for replication. Thus, it emerges as an attractive target for drug design. We report here the 2.5 angstrom resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The protease has a chymotrypsin-like fold and features a tetrahedrally coordinated metal ion distal to the active site. The NS4A peptide intercalates within a beta sheet of the enzyme core.

摘要

据估计，全球约1%的人口感染了丙型肝炎病毒（HCV），而对于慢性丙型肝炎的衰弱进展，目前尚无广泛有效的治疗方法。位于HCV NS3蛋白内的一种丝氨酸蛋白酶在四个特定位点加工病毒多聚蛋白，被认为是复制所必需的。因此，它成为药物设计的一个有吸引力的靶点。我们在此报告了与合成的NS4A激活肽复合的NS3蛋白酶结构域的2.5埃分辨率X射线晶体结构。该蛋白酶具有类胰凝乳蛋白酶的折叠结构，在活性位点远端有一个四面体配位的金属离子。NS4A肽插入酶核心的一个β折叠中。