4m17: Difference between revisions
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==Crystal Structure of Surfactant Protein-D D325A/R343V mutant== | |||
<StructureSection load='4m17' size='340' side='right'caption='[[4m17]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4m17]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M17 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M17 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.096Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | |||
<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> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/SFTPD_HUMAN SFTPD_HUMAN] Contributes to the lung's defense against inhaled microorganisms. May participate in the extracellular reorganization or turnover of pulmonary surfactant. Binds strongly maltose residues and to a lesser extent other alpha-glucosyl moieties. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4m17" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Allen K]] | |||
[[Category: Cafarella TR]] | |||
[[Category: Calin O]] | |||
[[Category: Crouch EC]] | |||
[[Category: Goh BC]] | |||
[[Category: Hartshorn KL]] | |||
[[Category: Rynkiewicz MJ]] | |||
[[Category: Schulten K]] | |||
[[Category: Seaton BA]] | |||
[[Category: Seeberger PH]] | |||
[[Category: White MR]] | |||
Latest revision as of 19:30, 20 September 2023
Crystal Structure of Surfactant Protein-D D325A/R343V mutantCrystal Structure of Surfactant Protein-D D325A/R343V mutant
Structural highlights
FunctionSFTPD_HUMAN Contributes to the lung's defense against inhaled microorganisms. May participate in the extracellular reorganization or turnover of pulmonary surfactant. Binds strongly maltose residues and to a lesser extent other alpha-glucosyl moieties. Publication Abstract from PubMedSurfactant 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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