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Protein Science, Vol 7, Issue 4 837-847, Copyright © 1998 by Cold Spring Harbor Laboratory Press

ARTICLE

Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: A 2.2 A resolution structure in a hexagonal crystal form

Y. YAN, Y. LI, S. MUNSHI, V. SARDANA, J. L. COLE, M. SARDANA, C. STEINKUEHLER, L. TOMEI, R. DE-FRANCESCO, L. C. KUO and Z. CHEN
Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania 19486

The crystal structure of the NS3 protease of the hepatitis C virus (BK strain) has been determined in the space group P6(3)22 to a resolution of 2.2 A. This protease is bound with a 14-mer peptide representing the central region of the NS4A protein. There are two molecules of the NS3(1-180)-NS4A(21'-34') complex per asymmetric unit. Each displays a familiar chymotrypsin-like fold that includes two {beta}-barrel domains and four short {alpha}-helices. The catalytic triad (Ser-139, His-57, and Asp-81) is located in the crevice between the {beta}-barrel domains. The NS4A peptide forms an almost completely enclosed peptide surface association with the protease. In contrast to the reported H strain complex of NS3 protease-NS4A peptide in a trigonal crystal form (Kim JL et al., 1996, Cell 87:343-355), the N-terminus of the NS3 protease is well-ordered in both molecules in the asymmetric unit of our hexagonal crystal form. The folding of the N-terminal region of the NS3 protease is due to the formation of a three-helix bundle as a result of crystal packing. When compared with the unbound structure (Love RA et al., 1996, Cell 87:331-342), the binding of the NS4A peptide leads to the ordering of the N-terminal 28 residues of the NS3 protease into a {beta}-strand and an {alpha}-helix and also causes local rearrangements important for a catalytically favorable conformation at the active site. Our analysis provides experimental support for the proposal that binding of an NS4A-mimicking peptide, which increases catalytic rates, is necessary but not sufficient for formation of a well-ordered, compact and, hence, highly active protease molecule.
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