4xw2
From Proteopedia
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==Structural basis for simvastatin competitive antagonism of complement receptor 3== | ==Structural basis for simvastatin competitive antagonism of complement receptor 3== | ||
<StructureSection load='4xw2' size='340' side='right' caption='[[4xw2]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='4xw2' size='340' side='right' caption='[[4xw2]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
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<table><tr><td colspan='2'>[[4xw2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XW2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xw2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XW2 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SIM:SIMVASTATIN+ACID'>SIM</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SIM:SIMVASTATIN+ACID'>SIM</scene></td></tr> | ||
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xw2 OCA], [http://pdbe.org/4xw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xw2 RCSB], [http://www.ebi.ac.uk/pdbsum/4xw2 PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xw2 OCA], [http://pdbe.org/4xw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xw2 RCSB], [http://www.ebi.ac.uk/pdbsum/4xw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xw2 ProSAT]</span></td></tr> |
</table> | </table> | ||
== Disease == | == Disease == | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/ITAM_HUMAN ITAM_HUMAN]] Integrin alpha-M/beta-2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles. It is identical with CR-3, the receptor for the iC3b fragment of the third complement component. It probably recognizes the R-G-D peptide in C3b. Integrin alpha-M/beta-2 is also a receptor for fibrinogen, factor X and ICAM1. It recognizes P1 and P2 peptides of fibrinogen gamma chain. | [[http://www.uniprot.org/uniprot/ITAM_HUMAN ITAM_HUMAN]] Integrin alpha-M/beta-2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement-coated particles. It is identical with CR-3, the receptor for the iC3b fragment of the third complement component. It probably recognizes the R-G-D peptide in C3b. Integrin alpha-M/beta-2 is also a receptor for fibrinogen, factor X and ICAM1. It recognizes P1 and P2 peptides of fibrinogen gamma chain. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The complement system is an important part of the innate immune response to infection, but may also cause severe complications during inflammation. Small molecule antagonists to complement receptor (CR)3 have been widely sought, but a structural basis for their mode of action is not available. We report here on the structure of the human CR3 ligand-binding I domain in complex with simvastatin. Simvastatin targets the metal ion-dependent adhesion site of the open, ligand-binding conformation of the CR3 I domain by direct contact with the chelated Mg2+ ion. Simvastatin antagonizes I domain binding to the complement fragments iC3b and C3d, but not to intercellular adhesion molecule-1. By virtue of the I domain's wide distribution in binding kinetics to ligands, it was possible to identify ligand binding kinetics as discriminator for simvastatin antagonism. In static cellular experiments, 15-25 muM simvastatin reduced adhesion by K562 cells expressing recombinant CR3 and by primary human monocytes, with an endogenous expression of this receptor. Application of force to adhering monocytes potentiated the effects of simvastatin where only 50-100 nM of the drug reduced the adhesion with 20-40% compared with untreated cells. The ability of simvastatin to target CR3 in its ligand binding-activated conformation is a novel mechanism to explain the known anti-inflammatory effects of this compound, in particular as this CR3 conformation is found in pro-inflammatory environments. Our report points to new designs of CR3 antagonists and opens new perspectives and identifies druggable receptors from characterization of the ligand binding kinetics in the presence of antagonists. | ||
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| + | Structural basis for simvastatin competitive antagonism of complement receptor 3.,Jensen MR, Bajic G, Zhang X, Laustsen AK, Koldso H, Skeby KK, Schiott B, Andersen GR, Vorup-Jensen T J Biol Chem. 2016 Jun 23. pii: jbc.M116.732222. PMID:27339893<ref>PMID:27339893</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 4xw2" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 18:15, 12 July 2016
Structural basis for simvastatin competitive antagonism of complement receptor 3
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