Measles remains a major public health concern worldwide. Measles virus (MV), the causative agent of measles, is highly contagious and transmissible. MV hemagglutinin protein (MV-H) recognizes and binds to specific cellular receptors to initiate the virus infection, and is one of the most important molecules mediating MV entry. Therefore, it is interesting to explore the recognition and binding modes between MV-H and its receptors.

Thus far, three MV-H receptors have been identified, including the signaling lymphocyte activation molecule (SLAM), the complement regulatory molecule CD46 and the nectin-4 protein of the cell adhesion molecule family.

CD46 is mainly recognized by the MV vaccine strains, while SLAM and nectin-4 are used by both the wild-type and the vaccine strain viruses. Nectin-4 is the most recently identified MV receptor and exhibits a much broader tissue/organ distribution than SLAM. Nevertheless, the molecular mechanism of nectin-4 recognition by MV-H remains elusive.

One division of Prof. GAO Fu (George F. Gao)’s laboratory is focused on the mechanisms of the viral cross-species transmission and immune recognition. As a step towards further elucidation of the MV pathogenesis and the rational design of anti-MV drugs, the complex structure of nectin-4 bound to MV-H was successfully solved by Prof. GAO and his colleagues.

In the complex structure, MV-H shows a cubic six-bladed (β1-β6) β-propeller fold and nectin-4 binds to the MV-H β4/β5 groove exclusively via its membrane distal immunoglobulin-like domain. The contact interface is dominated by hydrophobic interactions.

In addition, a di-residue motif consisting of a phenylalanine and a proline on the F-G loop of nectin-4 inserts into a hydrophobic pocket centered in the β4/β5 groove of MV-H, representing a key factor determining the MV-H/nectin-4 engagement (Figure). The identified hydrophobic pocket also plays a key role in the MV-H recognition of SLAM and CD46, based on their complex structures. This implies that small molecules targeting the pocket should disrupt the interaction of MV-H with all thus-far identified receptors.

It is still an urgent issue to search for effective anti-viral drugs for measles treatment. The viral entry process represents one of the best drug targets. This study clearly elucidates the molecular mechanism on the MV-H/nectin-4 recognition and would facilitate rational design of MV entry inhibitors.

These results were published in the nature series journal Nature Structural & Molecular Biology in December.

The complex structure and key binding features between MV-H and nectin-4 (Image by Prof. GAO’s lab)