Molecular Mechanisms of Viral and Host Cell Substrate Recognition by Hepatitis C Virus NS3/4A Protease

Journal Article · Tue Aug 16 04:00:00 EDT 2011 · J. Virol.

DOI:https://doi.org/10.1128/JVI.00377-11· OSTI ID:1022256

Romano, Keith P; Laine, Jennifer M; Deveau, Laura M; Cao, Hong; Massi, Francesca; Schiffer, Celia A ^[1]

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1. UMASS, MED

Hepatitis C NS3/4A protease is a prime therapeutic target that is responsible for cleaving the viral polyprotein at junctions 3-4A, 4A4B, 4B5A, and 5A5B and two host cell adaptor proteins of the innate immune response, TRIF and MAVS. In this study, NS3/4A crystal structures of both host cell cleavage sites were determined and compared to the crystal structures of viral substrates. Two distinct protease conformations were observed and correlated with substrate specificity: (i) 3-4A, 4A4B, 5A5B, and MAVS, which are processed more efficiently by the protease, form extensive electrostatic networks when in complex with the protease, and (ii) TRIF and 4B5A, which contain polyproline motifs in their full-length sequences, do not form electrostatic networks in their crystal complexes. These findings provide mechanistic insights into NS3/4A substrate recognition, which may assist in a more rational approach to inhibitor design in the face of the rapid acquisition of resistance.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: DOE - BASIC ENERGY SCIENCESNIHOTHER U.S. STATES
• OSTI ID: 1022256
• Journal Information: J. Virol., Journal Name: J. Virol. Journal Issue: (13) ; 07, 2011 Vol. 85; ISSN JOVIAM; ISSN 0022-538X
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CLEAVAGE
CRYSTAL STRUCTURE
DESIGN
ELECTROSTATICS
HEPATITIS
PROTEINS
SPECIFICITY
SUBSTRATES
TARGETS