4M17

Crystal Structure of Surfactant Protein-D D325A/R343V mutant

Summary for 4M17

• Entry DOI: 10.2210/pdb4m17/pdb
• Related: 4M18
• Descriptor: Pulmonary surfactant-associated protein D, CALCIUM ION (3 entities in total)
• Functional Keywords: surfactant protein, carbohydrate recognition domain, lectin, sugar binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix: P35247
• Total number of polymer chains: 12
• Total formula weight: 192023.02

Authors

Goh, B.C.,Rynkiewicz, M.J.,Cafarella, T.R.,White, M.R.,Hartshorn, K.L.,Allen, K.,Crouch, E.C.,Calin, O.,Seeberger, P.H.,Schulten, K.,Seaton, B.A. (deposition date: 2013-08-02, release date: 2013-12-04, Last modification date: 2023-09-20)

Primary citation

Goh, B.C.,Rynkiewicz, M.J.,Cafarella, T.R.,White, M.R.,Hartshorn, K.L.,Allen, K.,Crouch, E.C.,Calin, O.,Seeberger, P.H.,Schulten, K.,Seaton, B.A.
Molecular mechanisms of inhibition of influenza by surfactant protein d revealed by large-scale molecular dynamics simulation.
Biochemistry, 52:8527-8538, 2013

PubMed Abstract: 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.

PubMed: 24224757
DOI: 10.1021/bi4010683

Experimental method

X-RAY DIFFRACTION (2.096 Å)