2k3u

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

spinqualitylabelsall models 2k3u Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2k3u is a 2 chain structure with sequence from Homo sapiens and Staphylococcus aureus subsp. aureus str. Newman. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 25 models Ligands: ACE, NH2, TYS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CHIPS_STAAE Involved in countering the first line of host defense mechanisms. Specifically inhibits the response of human neutrophils and monocytes to complement anaphylatoxin C5a and formylated peptides, like N-formyl-methionyl-leucyl-phenylalanine (fMLP). Acts by binding directly to the C5a receptor (C5aR) and formylated peptide receptor (FPR), thereby blocking the C5a- and fMLP-induced calcium responses. Prevents phagocytosis of the bacterium. Publication Abstract from PubMed 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. Structure of the tyrosine-sulfated C5a receptor N terminus in complex with chemotaxis inhibitory protein of Staphylococcus aureus.,Ippel JH, de Haas CJ, Bunschoten A, van Strijp JA, Kruijtzer JA, Liskamp RM, Kemmink J J Biol Chem. 2009 May 1;284(18):12363-72. Epub 2009 Feb 27. PMID:19251703 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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