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| | ==Crystal structure of ClfA in complex with the Fab fragment of Tefibazumab== | | ==Crystal structure of ClfA in complex with the Fab fragment of Tefibazumab== |
| - | <StructureSection load='5jq6' size='340' side='right' caption='[[5jq6]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='5jq6' size='340' side='right'caption='[[5jq6]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5jq6]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JQ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JQ6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5jq6]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JQ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JQ6 FirstGlance]. <br> |
| - | </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=5jq6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jq6 OCA], [http://pdbe.org/5jq6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jq6 RCSB], [http://www.ebi.ac.uk/pdbsum/5jq6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jq6 ProSAT]</span></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]] 2.4Å</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=5jq6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jq6 OCA], [https://pdbe.org/5jq6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jq6 RCSB], [https://www.ebi.ac.uk/pdbsum/5jq6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jq6 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/CLFA_STAAE CLFA_STAAE] Cell surface-associated protein implicated in virulence. Promotes bacterial attachment exclusively to the gamma-chain of human fibrinogen. Induces formation of bacterial clumps, which diminish the ability of group IIA phospholipase A2 to cause bacterial phospholipid hydrolysis and killing. Significantly decreases macrophage phagocytosis possibly thanks to the clumps, clumped bacteria being too large to be phagocytosed. Dominant factor responsible for human platelet aggregation, which may be an important mechanism for initiating infective endocarditis. Enhances spleen cell proliferative response in vitro, contributing significantly to the immunostimulatory activity of S.aureus.<ref>PMID:10225887</ref> <ref>PMID:11292731</ref> <ref>PMID:12010496</ref> <ref>PMID:14998517</ref> |
| | <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 5jq6" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5jq6" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Ganesh, V K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Aurexis]] | + | [[Category: Large Structures]] |
| - | [[Category: Clumping factor some]] | + | [[Category: Mus musculus]] |
| - | [[Category: Fibrinogen]] | + | [[Category: Staphylococcus aureus]] |
| - | [[Category: Immune system]] | + | [[Category: Ganesh VK]] |
| - | [[Category: Mscramm]]
| + | |
| - | [[Category: Staphylococcal infection]]
| + | |
| - | [[Category: Tefibazumab]]
| + | |
| Structural highlights
Function
CLFA_STAAE Cell surface-associated protein implicated in virulence. Promotes bacterial attachment exclusively to the gamma-chain of human fibrinogen. Induces formation of bacterial clumps, which diminish the ability of group IIA phospholipase A2 to cause bacterial phospholipid hydrolysis and killing. Significantly decreases macrophage phagocytosis possibly thanks to the clumps, clumped bacteria being too large to be phagocytosed. Dominant factor responsible for human platelet aggregation, which may be an important mechanism for initiating infective endocarditis. Enhances spleen cell proliferative response in vitro, contributing significantly to the immunostimulatory activity of S.aureus.[1] [2] [3] [4]
Publication Abstract from PubMed
The Staphylococcus aureus fibrinogen binding MSCRAMM (Microbial Surface Components Recognizing Adhesive Matrix Molecules), ClfA (clumping factor A) is an important virulence factor in staphylococcal infections and a component of several vaccines currently under clinical evaluation. The mouse monoclonal antibody aurexis (also called 12-9), and the humanized version tefibazumab are therapeutic monoclonal antibodies targeting ClfA that in combination with conventional antibiotics were effective in animal models but showed less impressive efficacy in a limited Phase II clinical trial. We here report the crystal structure and a biochemical characterization of the ClfA/tefibazumab (Fab) complex. The epitope for tefibazumab is located to the "top" of the N3 subdomain of ClfA and partially overlaps with a previously unidentified second binding site for fibrinogen. A high-affinity binding of ClfA to fibrinogen involves both an interaction at the N3 site and the previously identified docking of the C-terminal segment of the fibrinogen gamma-chain in the N2N3 trench. Although tefibazumab binds ClfA with high affinity we observe a modest IC50 value for the inhibition of fibrinogen binding to the MSCRAMM. This observation, paired with a common natural occurring variant of ClfA that is not effectively recognized by the mAb, may partly explain the modest effect tefibazumab showed in the initial clinic trail. This information will provide guidance for the design of the next generation of therapeutic anti-staphylococcal mAbs targeting ClfA.
Lessons from the Crystal Structure of the S. aureus Surface Protein Clumping Factor A in Complex With Tefibazumab, an Inhibiting Monoclonal Antibody.,Ganesh VK, Liang X, Geoghegan JA, Cohen AL, Venugopalan N, Foster TJ, Hook M EBioMedicine. 2016 Nov;13:328-338. doi: 10.1016/j.ebiom.2016.09.027. Epub 2016, Oct 1. PMID:27789272[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dominiecki ME, Weiss J. Antibacterial action of extracellular mammalian group IIA phospholipase A2 against grossly clumped Staphylococcus aureus. Infect Immun. 1999 May;67(5):2299-305. PMID:10225887
- ↑ Siboo IR, Cheung AL, Bayer AS, Sullam PM. Clumping factor A mediates binding of Staphylococcus aureus to human platelets. Infect Immun. 2001 May;69(5):3120-7. PMID:11292731 doi:http://dx.doi.org/10.1128/IAI.69.5.3120-3127.2001
- ↑ O'Brien L, Kerrigan SW, Kaw G, Hogan M, Penades J, Litt D, Fitzgerald DJ, Foster TJ, Cox D. Multiple mechanisms for the activation of human platelet aggregation by Staphylococcus aureus: roles for the clumping factors ClfA and ClfB, the serine-aspartate repeat protein SdrE and protein A. Mol Microbiol. 2002 May;44(4):1033-44. PMID:12010496
- ↑ Palmqvist N, Patti JM, Tarkowski A, Josefsson E. Expression of staphylococcal clumping factor A impedes macrophage phagocytosis. Microbes Infect. 2004 Feb;6(2):188-95. PMID:14998517 doi:http://dx.doi.org/10.1016/j.micinf.2003.11.005
- ↑ Ganesh VK, Liang X, Geoghegan JA, Cohen AL, Venugopalan N, Foster TJ, Hook M. Lessons from the Crystal Structure of the S. aureus Surface Protein Clumping Factor A in Complex With Tefibazumab, an Inhibiting Monoclonal Antibody. EBioMedicine. 2016 Nov;13:328-338. doi: 10.1016/j.ebiom.2016.09.027. Epub 2016, Oct 1. PMID:27789272 doi:http://dx.doi.org/10.1016/j.ebiom.2016.09.027
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