On March 7th, «Protein & Cell» online published the new work from Prof. Bo OuYang’s group and Prof. James J. Chou’s group in National Center for Protein Science·Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, entitled “Structural Basis of Interaction between the Hepatitis C Virus p7 Channel and its Blocker Hexamethylene Amiloride”.
Hepatitis C virus (HCV) infection is a rising global health problem. The p7 protein is the only viroporin encoded by the HCV genome and has been sought after as a potential anti-HCV drug target. The ion channel activity of p7 can be blocked by several inhibitors, including rimantadine, hexamethylene amiloride (HMA), and long alkylchain iminosugar derivatives. Previous structural studies of the p7 channel from HCV genotype 5a revealed a hexameric funnel-like structure and suggested that rimantadine binds to peripheral pockets of the channel and inhibit the channel via an allosteric mechanism.
Here under the guidance of Prof. Bo OuYang and James J. Chou, Ph.D candidate Linlin Zhao determined the binding site of HMA, which is a stronger inhibitor, using nuclear magnetic resonance (NMR). NMR data show that HMA binds to a different peripheral pocket of the p7 channel than rimantadine, while both inhibitors induce very similar long-range conformational changes near the narrow opening of the cavity. MD simulations, performed by Shuqing Wang from Tianjin Medical University, further defined HMA binding by showing the interactions between Lys33, Leu36 and Leu45 with the amiloride group of HMA. Although different sites, HMA and rimantadine inhibit the p7 channel via an allosteric mechanism, either by restricting movement of helices needed for ion flow or by inducing structural rearrangements that block ion conduction, or both. These understanding of the structural basis in inhibitor binding of HCV p7 provides a future direction for structure-guided inhibitor design.
This work was supported by National Natural Science Foundation of China, the strategic Priority Research Program of the Chinese Academy of Sciences, National Institutes of Health Grant and sponsored by the Shanghai Pujiang Program (to B. O.).
CONTACT:
OUYANG BO, Principal Investigator, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Email: ouyang@sibcb.ac.cn.
Phone: +86-21-20778058
Figure. Comparison between adamantane binding site and HMA binding site of HCV p7 channels. (Image provided by Wang Shuqing from Tianjin University)
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