Molecular Mechanisms of Inhibition of Influenza by Surfactant Protein D Revealed by Large-Scale Molecular Dynamics Simulation
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- 作者：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 ; Barbara A. Seaton
- 刊名：Biochemistry
- 出版年：2013
- 出版时间：November 26, 2013
- 年：2013
- 卷：52
- 期：47
- 页码：8527-8538
- 全文大小：507K
- 年卷期：v.52,no.47(November 26, 2013)
- ISSN：1520-4995
文摘
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鈥揗an9 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鈥揌A 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.