X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs

The three-dimensional structures of avian H5 and swine H9 influenza hemaggl utinins (HAS) from viruses closely related to those that caused outbreaks o f human disease in Hong Kong in 1997 and 1999 were determined bound to avia n and human cell receptor analogs, Emerging influenza pandemics have been a ccompanied by the evolution of receptor-binding specificity from the prefer ence of avian viruses for sialic acid receptors in alpha2,3 linkage to the preference of human viruses for alpha2,6 linkages. The four new structures show that HA binding sites specific for human receptors appear to be wider than those preferring avian receptors and how avian and human receptors are distinguished by atomic contacts at the glycosidic linkage. alpha2,3-Linke d sialosides bind the avian HA in a trans conformation to form an alpha2,3 linkage-specific motif, made by the glycosidic oxygen and 4-OH of the penul timate galactose, that is complementary to the hydrogen-bonding capacity of Gln-226, an avian-specific residue. alpha2,6-Linked sialosides bind in a c is conformation, exposing the glycosidic oxygen to solution and nonpolar at oms of the receptor to Leu-226, a human-specific residue. The new structure s are compared with previously reported crystal structures of HA/sialoside complexes of the H3 subtype that caused the 1968 Hong Kong Influenza virus pandemic and analyzed in relation to HA sequences of all 15 subtypes and to receptor affinity data to make clearer how receptor-binding sites of HAS f rom avian viruses evolve as the virus adapts to humans.