Protein homology modeling and structure-function relationship of 2009 swine influenza virus hemagglutinin (HA1): more human than swine (original) (raw)
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Journal of Virology, 2012
brane fusion. The HA receptor-binding specificity is a key determinant for the host range and transmissibility of influenza viruses. In human pandemics of the 20th century, the HA normally has acquired specificity for human-like receptors before widespread infection. Crystal structures of the H1 HA from the 2009 human pandemic (A/California/04/2009 [CA04]) in complex with human and avian receptor analogs reveal conserved recognition of the terminal sialic acid of the glycan ligands. However, favorable interactions beyond the sialic acid are found only for ␣2-6-linked glycans and are mediated by Asp190 and Asp225, which hydrogen bond with Gal-2 and GlcNAc-3. For ␣2-3-linked glycan receptors, no specific interactions beyond the terminal sialic acid are observed. Our structural and glycan microarray analyses, in the context of other high-resolution HA structures with ␣2-6and ␣2-3-linked glycans, now elucidate the structural basis of receptor-binding specificity for H1 HAs in human and avian viruses and provide a structural explanation for the preference for ␣2-6 siaylated glycan receptors for the 2009 pandemic swine flu virus.
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...
Journal of Molecular Modeling, 2012
D222G mutation of the hemagglutinin (HA) is of special interest because of its close association with the enhanced virulence of 2009 pandemic influenza A (H1N1) virus through the increased binding affinity to α2,3-linked sialylated glycan receptors. However, there is still a lack of detailed understanding about the molecular mechanism of this enhanced virulence. Here, molecular dynamics simulation and binding free energy calculation were performed to explore the altered glycan receptor binding mechanism of HA upon the D222G mutation by studying the interaction of one α2,3-linked sialylglycan (sequence: SIA-GAL-NAG) with the wild type and D222G mutated HA. The binding free energy calculation based on the molecular mechanics generalized Born surface area (MM-GBSA) method indicates that the D222G mutated HA has a much stronger binding affinity with the studied α2,3-linked glycan than the wild type. This is consistent with the experimental result. The increased binding free energy of D222G mutant mainly comes from the increased energy contribution of Gln223. The structural analysis proves that the altered electrostatic potential of receptor binding domain (RBD) and the increased flexibility of 220-loop are the essential reasons leading to the increased affinity of HA to α2,3-linked sialic acid glycans. The obtained results of this study have allowed a deeper understanding of the receptor recognition mechanism and the pathogenicity of influenza virus, which will be valuable to the structure-based inhibitors design targeting influenza virus entry process.
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...
Structural Analysis of the Hemagglutinin from the Recent 2013 H7N9 Influenza Virus
Journal of Virology, 2013
In March 2013, the Chinese Center for Disease Control and Prevention reported human infections with an H7N9 influenza virus, and by 20 July 2013, the numbers of laboratory-confirmed cases had climbed to 134, including 43 fatalities and 127 hospitalizations. The newly emerging H7N9 viruses constitute an obvious public health concern because of the apparent severity of this outbreak. Here we focus on the hemagglutinins (HAs) of these viruses and assess their receptor binding phenotype in relation to previous HAs studied. Glycan microarray and kinetic analyses of recombinant A(H7N9) HAs were performed to compare the receptor binding profile of wild-type receptor binding site variants at position 217, a residue analogous to one of two positions known to switch avian to human receptor preference in H2N2 and H3N2 viruses. Two recombinant A(H7N9) HAs were structurally characterized, and a mutational study of the receptor binding site was performed to analyze important residues that can affect receptor preference and affinity. Results highlight a weak human receptor preference of the H7N9 HAs, suggesting that these viruses require further adaptation in order to adapt fully to humans. FIG 3 LSTb binding to SH-2. (A) The 2fo-fc electron density map (contoured at 1 and shown in blue) for LSTb bound to SH-2. (B) Interactions of the LSTb glycan with the SH-2 RBS. SH-2 is shown as cartoons, while LSTb and interacting HA residues are shown as sticks. Black dashed lines indicate hydrogen bonds.
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.
Molecular insights into human receptor binding to 2009 H1N1 influenza A hemagglutinin
Monatshefte für Chemie - Chemical Monthly, 2010
The current pandemic of the viral 2009 H1N1 influenza and its sustained human-human transmission has raised global concern for human health. The binding of the viral glycoprotein hemagglutinin (HA) and the human a-2,6-linked sialopentasaccharide (SIA-2,6-GAL) host cell receptor is a critical step in the viral replication cycle. Here, the complex structure of the 2009 H1N1 HA bound to the SIA-2,6-GAL sialopentasaccharide receptor was constructed by using homology modeling and molecular dynamic simulations. The receptor was found to fit very well within the HA binding pocket and formed hydrogen bonds with the residues of the 130-loop, 190-helix, and 220-loop. Most receptor binding residues play a significant role in stabilizing the protein-receptor complex with major contributions being provided by V135, T136, A137, K222, and Q226. The results are similar to the human SIA-2,6-GAL sialopentasaccharide receptor binding to H1 HA subtype, but are slightly different from those of H3, H5, and H9 HAs.
Structure and Receptor Complexes of the Hemagglutinin from a Highly Pathogenic H7N7 Influenza Virus
Journal of Virology, 2012
Recurrence of highly pathogenic avian influenza (HPAI) virus subtype H7 in poultry continues to be a public health concern. In 2003, an HPAI H7N7 outbreak in the Netherlands infected 89 people in close contact with affected poultry and resulted in one fatal case. In previous studies, the virus isolated from this fatal case, A/Netherlands/219/2003 (NL219) caused a lethal infection in mouse models and had increased replication efficiency and a broader tissue distribution than nonlethal isolates from the same outbreak. A mutation which introduces a potential glycosylation site at Asn123 in the NL219 hemagglutinin was postulated to contribute to the pathogenic properties of this virus. To study this further, we have expressed the NL219 hemagglutinin in a baculovirus expression system and performed a structural analysis of the hemagglutinin in complex with avian and human receptor analogs. Glycan microarray and kinetic analysis were performed to compare the receptor binding profile of the wild-type recombinant NL219 HA to a variant with a threonine-to-alanine mutation at position 125, resulting in loss of the glycosylation site at Asn123. The results suggest that the additional glycosylation sequon increases binding affinity to avian-type ␣2-3-linked sialosides rather than switching to a human-like receptor specificity and highlight the mechanistic diversity of these pathogens, which calls attention to the need for further studies to fully understand the unique properties of these viruses.
Structural and Functional Studies of Influenza Virus A/H6 Hemagglutinin
PLOS ONE, 2015
In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human-infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs. Our results revealed that in the presence of HA 1 Q226, the triad of HA 1 S137, E190 and G228 in GD H6 HA allows the binding to both avian-and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA 1 226 of H2 and H3 HAs when binding to human-like receptors. Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA 1 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance.