Structural studies on hepatitis C virus (HCV) NS5A and its molecular interaction with CypA

Hepatitis C virus infection is a worldwide issue and its NS5A protein interacts with host Cyclophilin A to play a crucial role in viral replication. To date, there is limited structural information for the intrinsically disordered NS5A protein. Here, low-resolution models of NS5A and NS5A-CypA from...

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Bibliographic Details
Main Author: Lee, Jia Jun
Other Authors: Yoon Ho Sup
Format: Theses and Dissertations
Language:English
Published: 2015
Subjects:
Online Access:http://hdl.handle.net/10356/65353
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Institution: Nanyang Technological University
Language: English
Description
Summary:Hepatitis C virus infection is a worldwide issue and its NS5A protein interacts with host Cyclophilin A to play a crucial role in viral replication. To date, there is limited structural information for the intrinsically disordered NS5A protein. Here, low-resolution models of NS5A and NS5A-CypA from small-angle X-ray scattering data were presented. The models suggest NS5A adopt an extended conformation and binding to CypA may induce NS5A-D1 dimerisation, similar to published data. NS5A-D2 and NS5A-D3 may bind CypA in random coil conformation. Residue P314 of NS5A-D2 is necessary and sufficient for this interaction. The CypA recognition site of NS5A-D2 binds to a region very close to CypA R55 residue, which is responsible for stabilization of the transition state for PPIase activity. A peptide of NS5A-D2 containing the CypA recognition site is able to perturb the conformation of CypA substrate binding cavity and inhibits HCV replication in HCV subgenomic replicon system.