Ippel, J.H., de Haas, C.J.C., Bunschoten, A., van Strijp, J.A.G., Kruijtzer, J.A.W., Liskamp, R.M.J. and Kemmink, J. (2009) Structure of the tyrosine-sulfated C5a receptor N terminus in complex with chemotaxis inhibitory protein of Staphylococcus aureus. Journal of Biological Chemistry, 284(18), pp. 12363-12372. (doi: 10.1074/jbc.M808179200)
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Abstract
Complement component C5a is a potent pro-inflammatory agent inducing chemotaxis of leukocytes toward sites of infection and injury. C5a mediates its effects via its G protein-coupled C5a receptor (C5aR). Although under normal conditions highly beneficial, excessive levels of C5a can be deleterious to the host and have been related to numerous inflammatory diseases. A natural inhibitor of the C5aR is chemotaxis inhibitory protein of <i>Staphylococcus aureus</i> (CHIPS). CHIPS is a 121-residue protein excreted by S. aureus. It binds the N terminus of the C5aR (residues 1-35) with nanomolar affinity and thereby potently inhibits C5a-mediated responses in human leukocytes. Therefore, CHIPS provides a starting point for the development of new anti-inflammatory agents. Two O-sulfated tyrosine residues located at positions 11 and 14 within the C5aR N terminus play a critical role in recognition of C5a, but their role in CHIPS binding has not been established so far. By isothermal titration calorimetry, using synthetic Tyr-11- and Tyr-14-sulfated and non-sulfated C5aR N-terminal peptides, we demonstrate that the sulfate groups are essential for tight binding between the C5aR and CHIPS. In addition, the NMR structure of the complex of CHIPS and a sulfated C5aR N-terminal peptide reveals the precise binding motif as well as the distinct roles of sulfated tyrosine residues sY11 and sY14. These results provide a molecular framework for the design of novel CHIPS-based C5aR inhibitors.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Liskamp, Professor Robert |
Authors: | Ippel, J.H., de Haas, C.J.C., Bunschoten, A., van Strijp, J.A.G., Kruijtzer, J.A.W., Liskamp, R.M.J., and Kemmink, J. |
College/School: | College of Science and Engineering > School of Chemistry |
Journal Name: | Journal of Biological Chemistry |
ISSN: | 0021-9258 |
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