Evolution of the receptor binding properties of the influenza A(H3N2) hemagglutinin (original) (raw)
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Proceedings of the National Academy of Sciences, 2001
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 α2,3 linkage to the preference of human viruses for α2,6 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. α2,3-Linked sialosides bind the avian HA in a trans conformation to form an α2,3 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. α...
Structural basis for receptor specificity of influenza B virus hemagglutinin
Proceedings of the National Academy of Sciences, 2007
Receptor-binding specificity of HA, the major surface glycoprotein of influenza virus, primarily determines the host ranges that the virus can infect. Influenza type B virus almost exclusively infects humans and contributes to the annual “flu” sickness. Here we report the structures of influenza B virus HA in complex with human and avian receptor analogs, respectively. These structures provide a structural basis for the different receptor-binding properties of influenza A and B virus HA molecules and for the ability of influenza B virus HA to distinguish human and avian receptors. The structure of influenza B virus HA with avian receptor analog also reveals how mutations in the region of residues 194 to 196, which are frequently observed in egg-adapted and naturally occurring variants, directly affect the receptor binding of the resultant virus strains. Furthermore, these structures of influenza B virus HA are compared with known structures of influenza A virus HAs, which suggests t...
The Structure and Receptor Binding Properties of the 1918 Influenza Hemagglutinin
Science, 2004
The 1918 influenza pandemic resulted in about 20 million deaths. This enormous impact, coupled with renewed interest in emerging infections, makes characterization of the virus involved a priority. Receptor binding, the initial event in virus infection, is a major determinant of virus transmissibilitythat, for influenza viruses, is mediated by the hemagglutinin (HA) membrane glycoprotein. We have determined the crystal structures of the HA from the 1918 virus and two closelyrelated HAs in complex with receptor analogs. Theyexplain how the 1918 HA, while retaining receptor binding site amino acids characteristic of an avian precursor HA, is able to bind human receptors and how, as a consequence, the virus was able to spread in the human population.
Journal of Virology, 2000
influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the avian virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of avian virus HAs into these species. The viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3SL-PAA and 6SLN-PAA, which contained, respectively, 3-sialyllactose (the receptor determinant preferentially recognized by avian influenza viruses) and 6-sialyl(N-acetyllactosamine) (the receptor determinant for human viruses). Avian and seal viruses bound 6SLN-PAA very weakly, whereas the earliest available human and swine epidemic viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q3L, increased binding to 6SLN-PAA, while among H1 swine viruses, the 190E3D and 225G3E mutations in the HA appeared important for the increased affinity of the viruses for 6SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the avian virus consensus sequence are also present in H1 human viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an avian virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.
Journal of Virology, 2005
The receptor binding specificity of influenza viruses may be important for host restriction of human and avian viruses. Here, we show that the hemagglutinin (HA) of the virus that caused the 1918 influenza pandemic has strain-specific differences in its receptor binding specificity. The A/South Carolina/1/18 HA preferentially binds the ␣2,6 sialic acid (human) cellular receptor, whereas the A/New York/1/18 HA, which differs by only one amino acid, binds both the ␣2,6 and the ␣2,3 sialic acid (avian) cellular receptors. Compared to the conserved consensus sequence in the receptor binding site of avian HAs, only a single amino acid at position 190 was changed in the A/New York/1/18 HA. Mutation of this single amino acid back to the avian consensus resulted in a preference for the avian receptor.
Avian and human receptor binding by hemagglutinins of influenza A viruses
Glycoconjugate Journal, 2006
An understanding of the structural determinants and molecular mechanisms involved in influenza A virus binding to human cell receptors is central to the identification of viruses that pose a pandemic threat. To date, only a limited number of viruses are known to have infected humans even sporadically, and this has recently included the virulent H5 and H7 avian viruses. We compare here the 3-dimensional structures of H5 and H7 hemagglutinins (HA) complexed with avian and human receptor analogues, to highlight regions within the receptor binding domains of these HAs that might prevent strong binding to the human receptor.
Crystal structures of influenza virus hemagglutinin in complex with high-affinity receptor
Structure, 1994
Background: The first step in influenza A virus infection involves attachment to cells through binding of viral hemagglutinin to cell-surface receptors containing ea-5-N-acetylneuraminic acid (sialic acid). The structures of soluble hemagglutinin in isolation and in complex with several low-affinity receptor analogs have been solved previously to approximately 3A resolution. To design effective, and possibly therapeutic, inhibitors of viral attachment we have determined the structure of hemagglutinin in complex with four high-affinity (10-fold to 100-fold higher affinity) sialic acid analogs at higher resolution. Results: In each crystal structure the sialic acid moiety is equivalently positioned in the receptor binding site but the substituent groups that differentiate the high-affinity analogs from each other interact with hydrophobic patches and polar residues adjacent to the binding site. Re-examination of the receptor binding site at 2.15 A resolution reveals several hydrophilic pockets and an apolar channel that adjoin the receptor binding site. Conclusions: The interactions observed in the structures of soluble hemagglutinin in complex with receptor analogs suggest explanations for the observed affinities of the analogs, designs for potential sialic acid analogs with even higher affinities, and ideas both for inhibiting membrane fusion and for circumventing evasion of inhibition by antigenic variation.
Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957
Proceedings of the National Academy of Sciences, 2009
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 bo...
Receptor binding specificity of recent human H3N2 influenza viruses
Virology Journal, 2007
Background Human influenza viruses are known to bind to sialic acid linked α2-6 to galactose, but the binding specificity beyond that linkage has not been systematically examined. H3N2 human influenza isolates lost binding to chicken red cells in the 1990s but viruses isolated since 2003 have re-acquired the ability to agglutinate chicken erythrocytes. We have investigated specificity of binding, changes in hemagglutinin sequence of the recent viruses and the role of sialic acid in productive infection. Results Viruses that agglutinate, or do not agglutinate, chicken red cells show identical binding to a Glycan Array of 264 oligosaccharides, binding exclusively to a subset of α2-6-sialylsaccharides. We identified an amino acid change in hemagglutinin that seemed to correlate with chicken red cell binding but when tested by mutagenesis there was no effect. Recombinant hemagglutinins expressed on Sf-9 cells bound chicken red cells but the released recombinant baculoviruses agglutinate...