Viral membrane fusion is a critical step in infection, facilitated by viral fusion proteins that undergo large-scale conformational changes to bring viral and host-cell membranes together. These proteins, though structurally diverse, share a common mechanism involving a ligand-triggered conformational change that lowers the kinetic barrier to membrane fusion. Examples include influenza virus hemagglutinin, flavivirus E protein, and vesicular stomatitis virus G protein. Fusion inhibitors can effectively block viral entry by targeting these proteins. The process of membrane fusion involves several steps: initial binding of the fusion protein to the target membrane, formation of an extended intermediate, collapse into a hemifusion stalk, and finally, formation of a fusion pore. The hemifusion intermediate is a key step, and its structure is often stalk-like. The fusion protein's structure typically includes a C-terminal transmembrane anchor and a hydrophobic fusion peptide or loop that interacts with the target membrane. These proteins are often trimeric in their active state. Influenza virus hemagglutinin undergoes a large conformational change at low pH, leading to the exposure of the fusion peptide and subsequent membrane fusion. The structure of the pre-fusion and post-fusion conformations has been determined, revealing the mechanism of fusion. Flavivirus E protein also undergoes conformational changes at low pH, with the fusion loop inserting into the target membrane. The vesicular stomatitis virus G protein has a reversible conformational change, with the fusion loops interacting with the target membrane. Fusion proteins from various viruses share common structural features and mechanisms, despite differences in their specific structures. The fusion process involves the formation of an extended intermediate, which collapses to form a hemifusion stalk and eventually a fusion pore. The energy released during this process helps overcome the kinetic barrier to membrane fusion. Fusion inhibitors, such as T-20, target the extended intermediate and can block viral entry. Structural studies of fusion proteins have provided insights into the mechanisms of membrane fusion and the development of antiviral drugs. Understanding these mechanisms is crucial for the design of effective antiviral therapies.Viral membrane fusion is a critical step in infection, facilitated by viral fusion proteins that undergo large-scale conformational changes to bring viral and host-cell membranes together. These proteins, though structurally diverse, share a common mechanism involving a ligand-triggered conformational change that lowers the kinetic barrier to membrane fusion. Examples include influenza virus hemagglutinin, flavivirus E protein, and vesicular stomatitis virus G protein. Fusion inhibitors can effectively block viral entry by targeting these proteins. The process of membrane fusion involves several steps: initial binding of the fusion protein to the target membrane, formation of an extended intermediate, collapse into a hemifusion stalk, and finally, formation of a fusion pore. The hemifusion intermediate is a key step, and its structure is often stalk-like. The fusion protein's structure typically includes a C-terminal transmembrane anchor and a hydrophobic fusion peptide or loop that interacts with the target membrane. These proteins are often trimeric in their active state. Influenza virus hemagglutinin undergoes a large conformational change at low pH, leading to the exposure of the fusion peptide and subsequent membrane fusion. The structure of the pre-fusion and post-fusion conformations has been determined, revealing the mechanism of fusion. Flavivirus E protein also undergoes conformational changes at low pH, with the fusion loop inserting into the target membrane. The vesicular stomatitis virus G protein has a reversible conformational change, with the fusion loops interacting with the target membrane. Fusion proteins from various viruses share common structural features and mechanisms, despite differences in their specific structures. The fusion process involves the formation of an extended intermediate, which collapses to form a hemifusion stalk and eventually a fusion pore. The energy released during this process helps overcome the kinetic barrier to membrane fusion. Fusion inhibitors, such as T-20, target the extended intermediate and can block viral entry. Structural studies of fusion proteins have provided insights into the mechanisms of membrane fusion and the development of antiviral drugs. Understanding these mechanisms is crucial for the design of effective antiviral therapies.