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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=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xw2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 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=4XW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.001Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ITGAM, CD11B, CR3A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xw2 ProSAT]</span></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=4xw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xw2 OCA], [https://pdbe.org/4xw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xw2 RCSB], [https://www.ebi.ac.uk/pdbsum/4xw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xw2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ITAM_HUMAN ITAM_HUMAN]] Genetic variations in ITGAM has been associated with susceptibility to systemic lupus erythematosus type 6 (SLEB6) [MIM:[http://omim.org/entry/609939 609939]]. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. | + | [https://www.uniprot.org/uniprot/ITAM_HUMAN ITAM_HUMAN] Genetic variations in ITGAM has been associated with susceptibility to systemic lupus erythematosus type 6 (SLEB6) [MIM:[https://omim.org/entry/609939 609939]. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. |
| | == 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. | + | [https://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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4xw2" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4xw2" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Integrin 3D structures|Integrin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Andersen, G R]] | + | [[Category: Large Structures]] |
| - | [[Category: Bajic, G]] | + | [[Category: Andersen GR]] |
| - | [[Category: Jensen, M R]] | + | [[Category: Bajic G]] |
| - | [[Category: Vorup-Jensen, T]] | + | [[Category: Jensen MR]] |
| - | [[Category: Complement receptor 3]] | + | [[Category: Vorup-Jensen T]] |
| - | [[Category: I domain]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Integrin]]
| + | |
| - | [[Category: Mac-1]]
| + | |
| - | [[Category: Protein-inhibitor complex]]
| + | |
| - | [[Category: Rossmann fold]]
| + | |
| - | [[Category: Statin]]
| + | |
| - | [[Category: Vwa]]
| + | |
| Structural highlights
Disease
ITAM_HUMAN Genetic variations in ITGAM has been associated with susceptibility to systemic lupus erythematosus type 6 (SLEB6) [MIM:609939. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system.
Function
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.
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jensen MR, Bajic G, Zhang X, Laustsen AK, Koldso H, Skeby KK, Schiott B, Andersen GR, Vorup-Jensen T. Structural basis for simvastatin competitive antagonism of complement receptor 3. J Biol Chem. 2016 Jun 23. pii: jbc.M116.732222. PMID:27339893 doi:http://dx.doi.org/10.1074/jbc.M116.732222
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