当前位置： SCI文献检索 > BIOCHEMISTRY期刊下所有文献 > Conformational changes in human hepatitis C virus NS3 protease upon binding of product-based inhibitors.

Conformational changes in human hepatitis C virus NS3 protease upon binding of product-based inhibitors.

Abstract：

:One of the most promising approaches to anti-hepatitis C virus drug discovery is the development of inhibitors of the virally encoded protease NS3. This chymotrypsin-like serine protease is essential for the maturation of the viral polyprotein, and processing requires complex formation between NS3 and its cofactor NS4A. Recently, we reported on the discovery of potent cleavage product-derived inhibitors [Ingallinella et al. (1998) Biochemistry 37, 8906-8914]. Here we study the interaction of these inhibitors with NS3 and the NS3/cofactor complex. Inhibitors bind NS3 according to an induced-fit mechanism. In the absence of cofactor different binding modes are apparent, while in the presence of cofactor all inhibitors show the same binding mode with a small rearrangement in the NS3 structure, as suggested by circular dichroism spectroscopy. These data are consistent with the hypothesis that NS4A complexation induces an NS3 structure that is already (but not entirely) preorganized for substrate binding not only for what concerns the S' site, as already suggested, but also for the S site. Inhibitor binding to the NS3/cofactor complex induces the stabilization of the enzyme structure as highlighted by limited proteolysis experiments. We envisage that this may occur through stabilization of the individual N-terminal and C-terminal domains where the cofactor and inhibitor, respectively, bind and subsequent tightening of the interdomain interaction in the ternary complex.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Bianchi E,Orrù S,Dal Piaz F,Ingenito R,Casbarra A,Biasiol G,Koch U,Pucci P,Pessi A

doi

10.1021/bi991220w

subject

Has Abstract

pub_date

1999-10-19 00:00:00

pages

13844-52

issue

42

eissn

0006-2960

issn

1520-4995

pii

bi991220w

journal_volume

38

pub_type

杂志文章

相关文献

BIOCHEMISTRY文献大全