Swine H9 and human H3 HA binding sites preferring α2,6 linkages are
wider than avian H5 preferring α2,3. The H9 swine (gray), H3 human
(green), and H5 avian (white) 226/228 loops are superimposed, showing
that the H5 avian 220s loop (Gln-226/Gly-228) is closer to the
opposing 130s loop than the H9 swine (Leu-226/Gly-228) or H3 human
(Leu-226/Ser-228). Contact between Ala-138 and the lower methyl group
of Leu-226 requires a more “open” site. The glycosidic oxygen of
sialic acid (atom colors) is labeled with an asterisk. A water molecule
(red sphere) mediates interactions between the amide group of Gly-228
and the 8- and 9-OHs of sialic acid in H9 swine and H5 avian HAs. The
hydroxyl group of Ser-228 “replaces” the water molecule to form a
hydrogen bond with 9-OH in the H3 human HA.