Substrate specificity of the hepatitis C virus serine protease NS3

Andrea Urbani, Elisabetta Bianchi, Frank Narjes, Anna Tramontano, Raffaele De Francesco, Christian Steinkühler, Antonello Pessi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)9204-9209
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number14
DOIs
Publication statusPublished - Apr 4 1997

ASJC Scopus subject areas

  • Biochemistry

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