ABSTRACT: A key question regarding the signaling mechanism for G protein-coupled receptors (GPCRs) is what triggers agonism versus antagonism. Peptide analogs derived from the chemokine, complement fragment 5 anaphylatoxin (C5a), can act as agonists or antagonists to the C5a receptor, a member of the GPCR family [Gerber, B. O., Meng, E. C., Dotsch, V., Baranski, T. J. & Bourne, H. R. (2001) J. Biol. Chem. 276, 3394-4000]. Recently, we showed that two Cys residues engineered near a proposed binding site in the C5a receptor on transmembrane helices III and VI can selectively and reversibly trap short Cys-containing 3-mer peptides derived from C5a by disulfide bond formation [Buck, E. A., Bourne, H. & Wells, J. A. (November 18, 2004) J. Biol. Chem., 10.1074/jbc.C400500200]. Here, a library of 10,000 co
