2K3U

Structure of the tyrosine-sulfated C5a receptor N-terminus in complex with the immune evasion protein CHIPS.

Summary for 2K3U

• Entry DOI: 10.2210/pdb2k3u/pdb
• Related: 1XEE
• NMR Information: BMRB: 15778
• Descriptor: Chemotaxis inhibitory protein, C5a anaphylatoxin chemotactic receptor 1 (2 entities in total)
• Functional Keywords: chemotaxis inhibitory protein (chips), sulfated tyrosine, gpcr membrane protein c5ar, anaphylotoxin c5a, staphylococcus aureus, complement cascade, secreted, virulence, immune system
• Biological source: Staphylococcus aureus subsp. aureus str. Newman; More
• Total number of polymer chains: 2
• Total formula weight: 13186.78

Authors

Ippel, J.H.,Bunschoten, A.,Kemmink, J.,Liskamp, R. (deposition date: 2008-05-16, release date: 2009-03-10, Last modification date: 2024-11-06)

Primary citation

Ippel, J.H.,de Haas, C.J.,Bunschoten, A.,van Strijp, J.A.,Kruijtzer, J.A.,Liskamp, R.M.,Kemmink, J.
Structure of the Tyrosine-sulfated C5a Receptor N Terminus in Complex with Chemotaxis Inhibitory Protein of Staphylococcus aureus.
J.Biol.Chem., 284:12363-12372, 2009

PubMed 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 Staphylococcus aureus (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.

PubMed: 19251703
DOI: 10.1074/jbc.M808179200

Experimental method

SOLUTION NMR