Abstract
The influenza glycoprotein hemagglutinin (HA) plays crucial roles in the early stage of virus infection, including receptor binding and membrane fusion. Therefore, HA is a potential target for developing anti-influenza drugs. Recently, we characterized a novel inhibitor of highly pathogenic H5N1 influenza virus, CL-385319, which specifically inhibits HA-mediated viral entry. Studies presented here identified the critical binding residues for CL-385319, which clustered in the stem region of the HA trimer by site-directed mutagenesis. Extensive computational simulations, including molecular docking, molecular dynamics simulations, molecular mechanics generalized Born surface area (MM_GBSA) calculations, charge density and Laplacian calculations, have been carried out to uncover the detailed molecular mechanism that underlies the binding of CL-385319 to H5N1 influenza virus HA. It was found that the recognition and binding of CL-385319 to HA proceeds by a process of “induced fit” whereby the binding pocket is formed during their interaction. Occupation of this pocket by CL-385319 stabilizes the neutral pH structure of hemagglutinin, thus inhibiting the conformational rearrangements required for membrane fusion. This “induced fit” pocket may be a target for structure-based design of more potent influenza fusion inhibitors.
Highlights
Enveloped viruses transfer their genetic material into cells by fusing their viral membrane with cellular membranes
These results strongly suggest that both M241 and F1102 may be critical for CL-385319 binding
To further investigate potential key residues on HA involved in the interaction with CL-385319, we selected amino acids surrounding M241 and F1102 located within a sphere of the radius of 3 A, according to the available crystal structure of HA, including K432, D462, G472,V482, K512, E1052, R1062 and T1072
Summary
Enveloped viruses transfer their genetic material into cells by fusing their viral membrane with cellular membranes. Membrane fusion is catalyzed by virus-specific envelope proteins. These viral envelope proteins have a common requirement for structural rearrangements during the fusion process. These conformational changes can be triggered by different stimuli, including acidification in low pH environment, as well as receptor and non-receptor binding. Class III fusion proteins are characterized by a combination of helical bundles and ß-sheets, including vesicular stomatitis virus protein G (VSV-G), baculovirus fusion protein gp, and others [5]. Influenza virus hemagglutinin is one of the best-characterized viral proteins which can mediate membrane fusion between influenza virus and target cell
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