3RC5

Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease

Summary for 3RC5

• Entry DOI: 10.2210/pdb3rc5/pdb
• Related: 3RC4 3RC6
• Descriptor: NS3/4A protease, Product MAVS, SULFATE ION, ... (5 entities in total)
• Functional Keywords: drug resistance, drug design, protease inhibitors, serine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepatitis C virus subtype 1a; More
• Total number of polymer chains: 2
• Total formula weight: 22631.86

Authors

Schiffer, C.A.,Romano, K.P. (deposition date: 2011-03-30, release date: 2011-05-04, Last modification date: 2024-10-30)

Primary citation

Romano, K.P.,Laine, J.M.,Deveau, L.M.,Cao, H.,Massi, F.,Schiffer, C.A.
Molecular mechanisms of viral and host cell substrate recognition by hepatitis C virus NS3/4A protease.
J.Virol., 85:6106-6116, 2011

PubMed Abstract: 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.

PubMed: 21507982
DOI: 10.1128/JVI.00377-11

Experimental method

X-RAY DIFFRACTION (1.6 Å)