Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957 - PubMed (original) (raw)

Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957

Junfeng Liu et al. Proc Natl Acad Sci U S A. 2009.

Abstract

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 compare it with the 1918 "Spanish Influenza" hemagglutinin, H1, and the 1968 "Hong Kong Influenza" hemagglutinin, H3, and show 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. By analyzing hemagglutinins of potential H2 avian precursors of the pandemic virus, we show that the human receptor can be bound by avian hemagglutinins that lack the human-specific mutations of H2 and H3 pandemic viruses, Gln-226Leu, and Gly-228Ser. We show how Gln-226 in the avian H2 receptor binding site, together with Asn-186, form hydrogen bond networks through bound water molecules to mediate binding to human receptor. We show that the human receptor adopts a very similar conformation in both human and avian hemagglutinin-receptor complexes. We also show that Leu-226 in the receptor binding site of human virus hemagglutinins creates a hydrophobic environment near the Sia-1-Gal-2 glycosidic linkage that favors binding of the human receptor and is unfavorable for avian receptor binding. We consider the significance for the development of pandemics, of the existence of avian viruses that can bind to both avian and human receptors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Ribbons representation of different H2 HA monomers and receptor binding sites. (A) Superposition of the monomers of two human H2 HAs: A/Singapore/1/57 and A/Japan/305/57 colored green and yellow respectively. (B) Three avian H2 HAs: A/ck/New York/29878/91 colored gray, A/dk/Ontario/77 colored in blue and A/ck/potsdam/4705/84 colored orange red. (C) Overlap of monomers of a human H2 HA colored in green and avian H2 HA colored in blue. The region highlighted by the gray ellipse at the top of the panel shows the receptor binding domain, an expanded version of which is shown in (D). Conserved residues such as Tyr-98, Ser-136, Trp-153, and His-183 are shown in stick representation together with other residues important in receptor binding specificity such as Asn-186, Glu-190, and Leu-194, as well as the Gln/Leu-226, Gly/Ser-228 pair.

Fig. 2.

Fig. 2.

Interactions of an avian H2 HA (upper panels) and a human H2 HA (lower panels) with avian and human receptor analogues. The three secondary structure elements of the binding site, the 130- and 220-loops and the 190-helix are labeled in this backbone representation together with some selected side chains in stick representation. The broken lines indicate potential hydrogen bond interaction. In all four panels, the sialosaccharides are colored yellow for carbon atoms, blue for nitrogen, and red for oxygen, water molecules are indicated by red spheres. A/dk/Ontario/77 H2 HA, colored blue, in complex with avian receptor, LSTa, (A) and human receptor, LSTc. (B). A/Singapore/1/57 H2 HA, colored in green, in complex with human receptor (C) and avian receptor (D). The black arrows in A, B, and C indicate that for the two human receptor complexes the Sia-1/Gal-2 linkage adopts a cis conformation, whereas for the avian complex it adopts a trans conformation.

Fig. 3.

Fig. 3.

Overlap of the receptor binding domains of H1, H2, and H3 HAs in complexes with receptor analogues. (A) The overlapped receptor binding sites of human HAs for H1 A/S.Carolina/1918, (blue), H2 A/Singapore/1/57, (yellow) and H3 A/Aichi/2/68, (22) (gray) in complex with human receptor analogue, LSTc. (B) The receptor binding domains of avian HAs for H1, A/dk/Alberta/76 (blue), H2, A/dk/Ontario/77 (yellow), and H3, A/dk/Ukraine/63 (25) (gray) in complex with human receptor analogue. The sialopentasaccharides are colored according to the HAs to which they are bound and some of the side-chains discussed in the text are shown in stick representation.

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