4OOW

HCV NS5B polymerase with a fragment of quercetagetin

Summary for 4OOW

• Entry DOI: 10.2210/pdb4oow/pdb
• Descriptor: RNA-directed RNA polymerase, CATECHOL (3 entities in total)
• Functional Keywords: enzyme, transferase
• Biological source: Hepatitis C virus (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : O92972
• Total number of polymer chains: 2
• Total formula weight: 129165.93

Authors

Guichou, J.F.,Ahmed-Belkacem, A.,Rozenn, B.,Nazim, N.,Hernandez, E.,Pallier, C.,Pawlotsky, J.M. (deposition date: 2014-02-04, release date: 2014-12-17, Last modification date: 2023-09-20)

Primary citation

Ahmed-Belkacem, A.,Guichou, J.F.,Brillet, R.,Ahnou, N.,Hernandez, E.,Pallier, C.,Pawlotsky, J.M.
Inhibition of RNA binding to hepatitis C virus RNA-dependent RNA polymerase: a new mechanism for antiviral intervention.
Nucleic Acids Res., 42:9399-9409, 2014

PubMed Abstract: The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) is a key target for antiviral intervention. The goal of this study was to identify the binding site and unravel the molecular mechanism by which natural flavonoids efficiently inhibit HCV RdRp. Screening identified the flavonol quercetagetin as the most potent inhibitor of HCV RdRp activity. Quercetagetin was found to inhibit RdRp through inhibition of RNA binding to the viral polymerase, a yet unknown antiviral mechanism. X-ray crystallographic structure analysis of the RdRp-quercetagetin complex identified quercetagetin's binding site at the entrance of the RNA template tunnel, confirming its original mode of action. This antiviral mechanism was associated with a high barrier to resistance in both site-directed mutagenesis and long-term selection experiments. In conclusion, we identified a new mechanism for non-nucleoside inhibition of HCV RdRp through inhibition of RNA binding to the enzyme, a mechanism associated with broad genotypic activity and a high barrier to resistance. Our results open the way to new antiviral approaches for HCV and other viruses that use an RdRp based on RNA binding inhibition, that could prove to be useful in human, animal or plant viral infections.

PubMed: 25053847
DOI: 10.1093/nar/gku632

Experimental method

X-RAY DIFFRACTION (2.57 Å)