2qff: Difference between revisions
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==Crystal structure of Staphylococcal Complement Inhibitor== | |||
<StructureSection load='2qff' size='340' side='right'caption='[[2qff]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2qff]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_MRSA252 Staphylococcus aureus subsp. aureus MRSA252]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QFF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QFF 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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=2qff FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qff OCA], [https://pdbe.org/2qff PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qff RCSB], [https://www.ebi.ac.uk/pdbsum/2qff PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qff ProSAT]</span></td></tr> | |||
</table> | |||
''' | == Function == | ||
[https://www.uniprot.org/uniprot/SCIN_STAAR SCIN_STAAR] Involved in countering the first line of host defense mechanisms. Efficiently inhibits opsonization, phagocytosis and killing of S.aureus by human neutrophils. Acts by binding and stabilizing human C3 convertases (C4b2a and C3bBb), leading to their inactivation. The convertases are no longer able to cleave complement C3, therefore preventing further C3b deposition on the bacterial surface and phagocytosis of the bacterium. Also prevents C5a-induced neutrophil responses (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== | == Publication Abstract from PubMed == | ||
The pathogenic bacterium Staphylococcus aureus counteracts the host immune defense by excretion of the 85 residue staphylococcal complement inhibitor (SCIN). SCIN inhibits the central complement convertases; thereby, it reduces phagocytosis following opsonization and efficiently blocks all downstream effector functions. In this study, we present the crystal structure of SCIN at 1.8 A resolution and the identification of its active site. Functional characterization of structure based chimeric proteins, consisting of SCIN and the structurally but nonfunctional homologue open reading frame-D, indicate an 18-residue segment (Leu-31-Gly-48) crucial for SCIN activity. In all complement activation pathways, chimeras lacking these SCIN residues completely fail to inhibit production of the potent mediator of inflammation C5a. Inhibition of alternative pathway-mediated opsonization (C3b deposition) and formation of the lytic membrane attack complex (C5b-9 deposition) are strongly reduced for these chimeras as well. For inhibition of the classical/lectin pathway-mediated C3b and C5b-9 deposition, the same residues are critical although additional sites are involved. These chimeras also display reduced capacity to stabilize the C3 convertases of both the alternative and the classical/lectin pathway indicating the stabilizing effect is pivotal for the complement inhibitory activity of SCIN. Because SCIN specifically and efficiently inhibits complement, it has a high potential in anti-inflammatory therapy. Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention. | The pathogenic bacterium Staphylococcus aureus counteracts the host immune defense by excretion of the 85 residue staphylococcal complement inhibitor (SCIN). SCIN inhibits the central complement convertases; thereby, it reduces phagocytosis following opsonization and efficiently blocks all downstream effector functions. In this study, we present the crystal structure of SCIN at 1.8 A resolution and the identification of its active site. Functional characterization of structure based chimeric proteins, consisting of SCIN and the structurally but nonfunctional homologue open reading frame-D, indicate an 18-residue segment (Leu-31-Gly-48) crucial for SCIN activity. In all complement activation pathways, chimeras lacking these SCIN residues completely fail to inhibit production of the potent mediator of inflammation C5a. Inhibition of alternative pathway-mediated opsonization (C3b deposition) and formation of the lytic membrane attack complex (C5b-9 deposition) are strongly reduced for these chimeras as well. For inhibition of the classical/lectin pathway-mediated C3b and C5b-9 deposition, the same residues are critical although additional sites are involved. These chimeras also display reduced capacity to stabilize the C3 convertases of both the alternative and the classical/lectin pathway indicating the stabilizing effect is pivotal for the complement inhibitory activity of SCIN. Because SCIN specifically and efficiently inhibits complement, it has a high potential in anti-inflammatory therapy. Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention. | ||
Staphylococcal complement inhibitor: structure and active sites.,Rooijakkers SH, Milder FJ, Bardoel BW, Ruyken M, van Strijp JA, Gros P J Immunol. 2007 Sep 1;179(5):2989-98. PMID:17709514<ref>PMID:17709514</ref> | |||
Staphylococcal complement inhibitor: structure and active sites., Rooijakkers SH, Milder FJ, Bardoel BW, Ruyken M, van Strijp JA, Gros P | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2qff" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus subsp. aureus MRSA252]] | |||
[[Category: Bardoel BW]] | |||
[[Category: Gros P]] | |||
[[Category: Milder FJ]] | |||
[[Category: Rooijakkers SHM]] | |||
[[Category: Ruyken M]] | |||
[[Category: Van Strijp JAG]] | |||
Latest revision as of 11:32, 30 October 2024
Crystal structure of Staphylococcal Complement InhibitorCrystal structure of Staphylococcal Complement Inhibitor
Structural highlights
FunctionSCIN_STAAR Involved in countering the first line of host defense mechanisms. Efficiently inhibits opsonization, phagocytosis and killing of S.aureus by human neutrophils. Acts by binding and stabilizing human C3 convertases (C4b2a and C3bBb), leading to their inactivation. The convertases are no longer able to cleave complement C3, therefore preventing further C3b deposition on the bacterial surface and phagocytosis of the bacterium. Also prevents C5a-induced neutrophil responses (By similarity). Publication Abstract from PubMedThe pathogenic bacterium Staphylococcus aureus counteracts the host immune defense by excretion of the 85 residue staphylococcal complement inhibitor (SCIN). SCIN inhibits the central complement convertases; thereby, it reduces phagocytosis following opsonization and efficiently blocks all downstream effector functions. In this study, we present the crystal structure of SCIN at 1.8 A resolution and the identification of its active site. Functional characterization of structure based chimeric proteins, consisting of SCIN and the structurally but nonfunctional homologue open reading frame-D, indicate an 18-residue segment (Leu-31-Gly-48) crucial for SCIN activity. In all complement activation pathways, chimeras lacking these SCIN residues completely fail to inhibit production of the potent mediator of inflammation C5a. Inhibition of alternative pathway-mediated opsonization (C3b deposition) and formation of the lytic membrane attack complex (C5b-9 deposition) are strongly reduced for these chimeras as well. For inhibition of the classical/lectin pathway-mediated C3b and C5b-9 deposition, the same residues are critical although additional sites are involved. These chimeras also display reduced capacity to stabilize the C3 convertases of both the alternative and the classical/lectin pathway indicating the stabilizing effect is pivotal for the complement inhibitory activity of SCIN. Because SCIN specifically and efficiently inhibits complement, it has a high potential in anti-inflammatory therapy. Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention. Staphylococcal complement inhibitor: structure and active sites.,Rooijakkers SH, Milder FJ, Bardoel BW, Ruyken M, van Strijp JA, Gros P J Immunol. 2007 Sep 1;179(5):2989-98. PMID:17709514[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References |
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