Mutant-selection experiments with the highly pathogenic avian influenza virus H5N1 have identified a virus that is transmissible to ferrets. In Nature, Xiong et al. report that the transmissible mutant virus has slightly higher binding affinity of hemagglutinin (HA) for its human receptor (sialic acid in α2,6-linkage to galactose on sugar side chains) and much less affinity for the avian receptor (sialic acid in α2,3-linkage). The crystal structure of the transmissible mutant HA in complex with receptor analogs shows that the mutant HA binds human receptors in the same folded-back conformation as did HA from viruses in the pandemics of 1918 (H1), 1957 (H2) and 1968 (H3), although the binding is weaker. This binding mode is different from that of wild-type H5 HA and arises from conformational changes due to a Q226L point substitution. The structural consequences of this substitution are similar to those of the pandemic viruses H2 and H3.

Nature 497, 392–396 (2013)