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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Molecular Mechanisms Of Viral And Host Cell Substrate Recognition By Hepatitis C Virus Ns3/4a Protease, Keith Romano, Jennifer Laine, Laura Deveau, Hong Cao, Francesca Massi, Celia Schiffer
Molecular Mechanisms Of Viral And Host Cell Substrate Recognition By Hepatitis C Virus Ns3/4a Protease, Keith Romano, Jennifer Laine, Laura Deveau, Hong Cao, Francesca Massi, Celia Schiffer
Celia A. Schiffer
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 …
Drug Resistance Against Hcv Ns3/4a Inhibitors Is Defined By The Balance Of Substrate Recognition Versus Inhibitor Binding, Keith P. Romano, Akbar Ali, William E. Royer, Celia A. Schiffer
Drug Resistance Against Hcv Ns3/4a Inhibitors Is Defined By The Balance Of Substrate Recognition Versus Inhibitor Binding, Keith P. Romano, Akbar Ali, William E. Royer, Celia A. Schiffer
Celia A. Schiffer
Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. …