Crystal structures of influenza virus hemagglutinin in complex with high-affinity receptor

Stanley Watowich, John J. Skehel, Don C. Wiley

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Background The first step in influenza A virus infection involves attachment to cells through binding of viral hemagglutinin to cell-surface receptors containing α-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 3å 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 å 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.

Original languageEnglish (US)
Pages (from-to)719-731
Number of pages13
JournalStructure
Volume2
Issue number8
DOIs
StatePublished - 1994
Externally publishedYes

Fingerprint

Hemagglutinins
N-Acetylneuraminic Acid
Orthomyxoviridae
Binding Sites
Viral Hemagglutinins
Antigenic Variation
Membrane Fusion
Influenza A virus
Cell Surface Receptors
Virus Diseases

Keywords

  • designed inhibitors
  • influenza virus hemagglutinin
  • protein- ligand interactions
  • receptor analogs
  • X-ray structure

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Crystal structures of influenza virus hemagglutinin in complex with high-affinity receptor. / Watowich, Stanley; Skehel, John J.; Wiley, Don C.

In: Structure, Vol. 2, No. 8, 1994, p. 719-731.

Research output: Contribution to journalArticle

Watowich, Stanley ; Skehel, John J. ; Wiley, Don C. / Crystal structures of influenza virus hemagglutinin in complex with high-affinity receptor. In: Structure. 1994 ; Vol. 2, No. 8. pp. 719-731.
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