X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs - PubMed (original) (raw)

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

Y Ha et al. Proc Natl Acad Sci U S A. 2001.

Abstract

The three-dimensional structures of avian H5 and swine H9 influenza hemagglutinins (HAs) from viruses closely related to those that caused outbreaks of human disease in Hong Kong in 1997 and 1999 were determined bound to avian and human cell receptor analogs. Emerging influenza pandemics have been accompanied by the evolution of receptor-binding specificity from the preference 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-Linked 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 penultimate galactose, that is complementary to the hydrogen-bonding capacity of Gln-226, an avian-specific residue. alpha2,6-Linked sialosides bind in a cis conformation, exposing the glycosidic oxygen to solution and nonpolar atoms of the receptor to Leu-226, a human-specific residue. The new structures 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 from avian viruses evolve as the virus adapts to humans.

PubMed Disclaimer

Figures

Figure 1

Conserved and variable interactions of H5 avian, H9 swine, and H3 human influenza virus subtype HAs with the sialic acid of pentasialosides. (a) 1997 H5 avian HA. (b) 1999 H9 swine HA. (c) 1968 H3 human HA. Red highlighted areas, conserved residues; yellow, sialic acid (Sia-1); red, oxygen; blue, nitrogen; filled HA atoms contact Sia-1; dashed lines, hydrogen bonds; red dashes, conserved hydrogen bonds.

Figure 2

The interaction of H5 and H9 influenza virus subtype HAs with avian α2,3 and human α2,6 sialosides. (a and_b_) Chemical formula of the pentasaccharides LSTa and LSTc. (c) Avian H5 HA with LSTa (α2,3) pentasaccharide bound. The α2,3 linkage is in trans conformation (bold arrow points up, 180° from the bond to the carboxylate of Sia-1). Hydrogen bonds (dashed lines) from Gln-226 to the α2,3-specific motif [4-OH of Gal-1 and glycosidic-O (at *) of trans linkage]. (d) Avian H5 HA with LSTc (α2,6) pentasaccharide bound. Only sialic acid of the ligand is ordered. (e) Swine H9 HA with LSTa (α2,3) pentasaccharide bound. Only two saccharides are ordered. The bound α2,3 linkage conformation is in cis conformation [bold arrow points nearly horizontal, 60° from the bond to the carboxylate of Sia-1; compare with bold arrow (trans) in_c_]. Contacts and hydrogen bonds (dotted lines) to Leu-226 and the carbonyl-O of residue 225 are shown. (f) Swine H9 HA with LSTc (α2,6) pentasaccharide bound. All five saccharides are ordered. The α2,6 linkage is in a cis conformation (bold arrow points nearly horizontal).

Figure 3

Atomic interactions between H5, H9, and H3 HAs and sialosides. (a) Potential hydrogen bonds (dashed red) between LSTc and the swine H9 HA. (b) Comparison of the binding of LSTc (α2,6) with the 1999 swine H9 (red) and 1968 human H3 (blue) subtype HA. Purple circles, common contacts; blue, H3 contacts; red, H9 contacts. (c) Comparison of the binding of LSTa (α2,3) with the 1997 avian H5 (green), 1999 swine H9 (red), and 1968 human H3 (blue) subtype HAs. Purple circles, common contacts; blue, H3 contacts; green, H5 contacts; red, H9 contacts.

Figure 4

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.

References

1. Who Memorandum. Bull W H O. 1980;58:585–591. - PMC - PubMed
1. Connor R J, Kawaoka Y, Webster R G, Paulson J C. Virology. 1994;205:17–23. - PubMed
1. Ito T, Couceiro J N, Kelm S, Baum L G, Krauss S, Castrucci M R, Donatelli I, Kida H, Paulson J C, Webster R G, et al. J Virol. 1998;72:7367–7373. - PMC - PubMed
1. Rogers G N, D'Souza B L. Virology. 1989;173:317–322. - PubMed
1. Baum L G, Paulson J C. Acta Histochem Suppl. 1990;40:35–38. - PubMed

X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs - PubMed (original) (raw)