Boon Chong Goh, Michael J. Rynkiewicz, Tanya R. Cafarella, Mitchell R. White,
Kevan L. Hartshorn, Kimberly Allen, Erika C. Crouch, Oliviana Calin, Peter H.
Seeberger, Klaus Schulten, and Barbara A. Seaton.
Molecular mechanisms of inhibition of influenza by surfactant protein
D revealed by large-scale molecular dynamics simulation.
Biochemistry, 52:8527-8538, 2013.
(PMC: PMC3927399)
GOH2013
Surfactant protein D (SP-D), a mammalian C-type lectin, is the primary innate inhibitor of
influenza A virus (IAV) in the lung. SP-D interactions with highly branched viral N-linked
glycans on hemagglutinin (HA), an abundant IAV envelope protein and critical virulence factor,
promote viral aggregation and neutralization through as yet unknown molecular mechanisms.
Two truncated human SP-D forms, wild-type (WT) and double mutant D325A+R343V,
representing neck and carbohydrate recognition domains are compared in this study. Whereas
both WT and D325A+R343V bind to isolated glycosylated HA, WT does not inhibit IAV in
neutralization assays; in contrast, D325A+R343V neutralization compares well with full-length
native SP-D. To elucidate the mechanism for these biochemical observations, we have solved
crystal structures of D325A+R343V in the presence and absence of a viral nonamannoside
(Man9). Based on the D325A+R343V/Man9 structure and other crystallographic data, models of
complexes between HA and WT or D325A+R343V were produced and subjected to molecular
dynamics. Simulations reveal that whereas WT and D325A+R343V both block the sialic acid
receptor site of HA, the D325A+R343V complex is more stable, with stronger binding due to
additional hydrogen bonds and hydrophobic interactions with HA residues. Furthermore, the
blocking mechanism of HA differs for WT and D325A+R343V due to alternate glycan binding
modes. The combined results suggest a mechanism through which the mode of SP-D/HA
interaction could significantly influence viral aggregation and neutralization. These studies
provide the first atomic-level molecular view of an innate host defense lectin inhibiting its viral
glycoprotein target.
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