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Volume 272, Number 14,
Issue of April 4, 1997
pp. 9204-9209
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Substrate Specificity of the Hepatitis C Virus Serine Protease
NS3
(Received for publication, November 11, 1995, and in revised form, January 19, 1997)
Andrea
Urbani
,
Elisabetta
Bianchi
,
Frank
Narjes
,
Anna
Tramontano
,
Raffaele
De Francesco
,
Christian
Steinkühler
and
Antonello
Pessi
From the Istituto di Ricerche di Biologia Molecolare (IRBM) P. Angeletti, Pomezia, Rome, Italy
The substrate specificity of a purified protein
encompassing the hepatitis C virus NS3 serine protease domain was
investigated by introducing systematic modifications, including
non-natural amino acids, into substrate peptides derived from the
NS4A/NS4B cleavage site. Kinetic parameters were determined in the
absence and presence of a peptide mimicking the protease co-factor NS4A (Pep4A). Based on this study we draw the following conclusions: (i) the
NS3 protease domain has an absolute requirement for a small residue in
the P1 position of substrates, thereby confirming previous modelling
predictions. (ii) Optimization of the P1 binding site occupancy
primarily influences transition state binding, whereas the occupancy of
distal binding sites is a determinant for both ground state and
transition state binding. (iii) Optimized contacts at distal binding
sites may contribute synergistically to cleavage efficiency.

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Copyright © 1997 by the American Society for Biochemistry and Molecular Biology.
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