Structure of measles virus hemagglutinin bound to its epithelial receptor nectin-4

Measles virus hemagglutinin (MVH) can bind to different cell surface receptors in the human host. CD46, the first identified MVH receptor, is used mainly by vaccine strains, whereas clinical strains can use SLAM on macrophages and dendritic cells and nectin-4 on epithelial cells. The crystal structure of MVH in complex with the outermost ectodomain of nectin-4 is now presented, revealing a potential target site for drug development. Measles virus is a major public health concern worldwide. Three measles virus cell receptors have been identified so far, and the structures of the first two in complex with measles virus hemagglutinin (MV-H) have been reported. Nectin-4 is the most recently identified receptor in epithelial cells, and its binding mode to MV-H remains elusive. In this study, we solved the structure of the membrane-distal domain of human nectin-4 in complex with MV-H. The structure shows that nectin-4 binds the MV-H β4-β5 groove exclusively via its N-terminal IgV domain; the contact interface is dominated by hydrophobic interactions. The binding site in MV-H for nectin-4 also overlaps extensively with those of the other two receptors. Finally, a hydrophobic pocket centered in the β4-β5 groove is involved in binding to all three identified measles virus receptors, representing a potential target for antiviral drugs.