4m17: Difference between revisions

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4m17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m17 OCA], [https://pdbe.org/4m17 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m17 RCSB], [https://www.ebi.ac.uk/pdbsum/4m17 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m17 ProSAT]</span></td></tr>

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.

Molecular mechanisms of inhibition of influenza by surfactant protein d revealed by large-scale molecular dynamics simulation.,Goh BC, Rynkiewicz MJ, Cafarella TR, White MR, Hartshorn KL, Allen K, Crouch EC, Calin O, Seeberger PH, Schulten K, Seaton BA Biochemistry. 2013 Nov 26;52(47):8527-38. doi: 10.1021/bi4010683. Epub 2013 Nov, 13. PMID:24224757<ref>PMID:24224757</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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