Journal
BIOCHEMISTRY
Volume 52, Issue 47, Pages 8527-8538Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi4010683
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Funding
- National Science Foundation [PHY0822613]
- National Institutes of Health (NIH) [9P41GM104601, PO1AI083222, RO1HL069031]
- XSEDE [MCA93S028]
- Max-Planck Society
- Marie Curie ITN FP7 Project CARMUSYS [PITN-GA-2008-213592]
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Surfactant protein D (SP-D), a mammalian C-type lectin, is the primary innate inhibitor of influenza A virus (IAV) in the lung. Interactions of SP-D 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 that of full-length native SP-D. To elucidate the mechanism for these biochemical observations, we have determined crystal structures of D325A +R343V in the presence and absence of a viral nonamannoside (Man9). On the basis of 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 caused by additional hydrogen bonds and hydrophobic interactions with HA residues. Furthermore, the blocking mechanism of HA differs for WT and D325A+R343V because of 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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