Crystal structures of influenza virus hemagglutinin in complex with high-affinity receptor analogs.
BACKGROUND
The first step in influenza A virus infection involves attachment to cells through binding of viral hemagglutinin to cell-surface receptors containing alpha-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 2.15A 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.
Watowich
S J
SJ
Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, MA 02138.
Skehel
J J
JJ
Wiley
D C
DC
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000737:chemistry*; D011991:Receptors, Virus / Q000737:chemistry*; D012794:Sialic Acids / Q000737:chemistry* / Q000378:metabolism; D013045:Species Specificity
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D008024:Ligands; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D012794:Sialic Acids; C028583:sialyloligosaccharide receptor