Gamblin lab

Structural Biology of Disease Processes Laboratory

: Influenza hemagglutinin

Structures of proteins investigated in the Gamblin lab

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The influenza virus surface glycoprotein hemagglutinin (HA) mediates receptor binding and membrane fusion in influenza infections.

The viruses that caused the three influenza pandemics of the twentieth century in 1918, 1957 and 1968 had distinct hemagglutinin receptor binding glycoproteins that had evolved the capacity to recognize human cell receptors.


We have determined the structure of the H2 hemagglutinin from the second pandemic, the “Asian Influenza” of 1957. We can compare it with the 1918 “Spanish Influenza” hemagglutinin, H1, and the 1968 “Hong Kong Influenza” hemagglutinin, H3. This shows that despite its close overall structural similarity to H1, and its more distant relationship to H3, the H2 receptor binding site is closely related to that of H3 hemagglutinin.

HA binds to sialic acids that form α2,3 or α2,6 linkages to galactose on cell surface glycoproteins and glycolipids. Avian influenza viruses preferentially bind α2,3-linked sialic acids, which predominate in the enteric tract of birds where the viruses replicate. Human influenza viruses preferentially bind to α2,6-linked sialic acids, which are the predominant form found in the human upper respiratory tract.

We have developed a quantitative assay to measure the binding of influenza viruses to immobilized sialic acids. Using instrumentation from Biacore and Fortebio, we are able to measure virus binding in real time to determine the specificity for different sugars. Analysis of different human, avian and swine influenza strains, as well as analysis of certain mutations in specific strains, reveals which viruses are able to bind well to human receptors.

By applying structural and biophysical techniques, we have recently shown how mutations to the sialic acid binding site of the avian H5N1 virus have allowed it to acquire a strong binding preference for the human receptor over the avian equivalent. The altered binding mode now resembles that previously observed in historically significant pandemic viruses.

Characterisation of the recently emerged H7N9 HA indicates that although it has also acquired higher affinity for the human receptor sialic acid, it has retained high affinity binding of the avian receptor. The retention of avian receptor binding will contribute to its low transmissibility due to sequestration by avian-like receptors in human mucins. Through these studies we are better able to understand the significance of mutations in this rapidly evolving virus.