Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3/4A protease
Authors
Romano, Keith P.Laine, Jennifer M.
Deveau, Laura M.
Cao, Hong
Massi, Francesca
Schiffer, Celia A.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2011-07-22Keywords
Adaptor Proteins, Signal TransducingCarrier Proteins
Catalytic Domain
Crystallization
Humans
Magnetic Resonance Spectroscopy
Membrane Proteins
Models, Molecular
Polyproteins
Protein Conformation
Static Electricity
Substrate Specificity
Viral Nonstructural Proteins
Biochemistry, Biophysics, and Structural Biology
Microbiology
Metadata
Show full item recordAbstract
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.Source
J Virol. 2011 Jul;85(13):6106-16. Epub 2011 Apr 20. Link to article on publisher's siteDOI
10.1128/JVI.00377-11Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26004PubMed ID
21507982Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1128/JVI.00377-11
Scopus Count
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