Comparative agonist/antagonist responses in mutant human C5a receptors define the ligand binding site

Higginbottom, Adrian, Cain, Stuart A., Woodruff, Trent M., Proctor, Lavinia M., Madala, Praveen K., Tyndall, Joel D. A., Taylor, Stephen M., Fairlie, David P. and Monk, Peter N. (2005) Comparative agonist/antagonist responses in mutant human C5a receptors define the ligand binding site. Journal of Biological Chemistry, 280 18: 17831-17840. doi:10.1074/jbc.M410797200

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Author Higginbottom, Adrian
Cain, Stuart A.
Woodruff, Trent M.
Proctor, Lavinia M.
Madala, Praveen K.
Tyndall, Joel D. A.
Taylor, Stephen M.
Fairlie, David P.
Monk, Peter N.
Title Comparative agonist/antagonist responses in mutant human C5a receptors define the ligand binding site
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2005-05-06
Year available 2005
Sub-type Article (original research)
DOI 10.1074/jbc.M410797200
Open Access Status File (Publisher version)
Volume 280
Issue 18
Start page 17831
End page 17840
Total pages 10
Editor Charlotte Steigers Sauer
Peter J. Stang
Place of publication Bethesda, MD
Publisher The American Society for Biochemistry and Molecular Biology,.
Language eng
Subject C1
250301 Organic Chemical Synthesis
780103 Chemical sciences
Abstract The C terminus is responsible for all of the agonist activity of C5a at human C5a receptors (C5aRs). In this report we have mapped the ligand binding site on the C5aR using a series of agonist and antagonist peptide mimics of the C terminus of C5a as well as receptors mutated at putative interaction sites ( Ile(116), Arg(175), Arg(206), Glu(199), Asp(282), and Val(286)). Agonist peptide 1 (Phe-Lys-Pro-D-cyclohexylalanine-cyclohexylalanine-D-Arg) can be converted to an antagonist by substituting the bulkier Trp for cyclohexylalanine at position 5 ( peptide 2). Conversely, mutation of C5aR transmembrane residue Ile(116) to the smaller Ala (I116A) makes the receptor respond to peptide 2 as an agonist (Gerber, B. O., Meng, E. C., Dotsch, V., Baranski, T. J., and Bourne, H. R. (2001) J. Biol. Chem. 276, 3394 - 3400). However, a potent cyclic hexapeptide antagonist, Phe-cyclo-[Orn-Pro-D-cyclohexylalanine-Trp-Arg] ( peptide 3), derived from peptide 2 and which binds to the same receptor site, remains a full antagonist at I116AC5aR. This suggests that although the residue at position 5 might bind near to Ile(116), the latter is not essential for either activation or antagonism. Arg(206) and Arg(175) both appear to interact with the C-terminal carboxylate of C5a agonist peptides, suggesting a dynamic binding mechanism that may be a part of a receptor activation switch. Asp(282) has been previously shown to interact with the side chain of the C-terminal Arg residue, and Glu(199) may also interact with this side chain in both C5a and peptide mimics. Using these interactions to orient NMR-derived ligand structures in the binding site of C5aR, a new model of the interaction between peptide antagonists and the C5aR is presented.
Keyword Cyclic Antagonists
Human Plasma
Biochemistry & Molecular Biology
Q-Index Code C1
Institutional Status UQ

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Created: Wed, 15 Aug 2007, 17:06:26 EST