 |
PDBsum entry 4m17
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Sugar binding protein
|
PDB id
|
|
|
|
4m17
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Molecular mechanisms of inhibition of influenza by surfactant protein d revealed by large-Scale molecular dynamics simulation.
|
|
|
Authors
|
|
B.C.Goh,
M.J.Rynkiewicz,
T.R.Cafarella,
M.R.White,
K.L.Hartshorn,
K.Allen,
E.C.Crouch,
O.Calin,
P.H.Seeberger,
K.Schulten,
B.A.Seaton.
|
|
|
Ref.
|
|
Biochemistry, 2013,
52,
8527-8538.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
