Biologically Active Conformer of the Effector Region of Human C5a and Modulatory Effects of N-Terminal Receptor Binding Determinants on Activity
- 1 March 1997
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (6), 877-884
- https://doi.org/10.1021/jm960727r
Abstract
A conformationally biased decapeptide agonist of human C5a (C5a65-74Y65,F67,P69,P71,d-Ala73 or YSFKPMPLaR) was used as a functional probe of the C5a receptor (C5aR) in order to understand the conformational features in the C-terminal effector region of C5a that are important for C5aR binding and signal transduction. YSFKPMPLaR was a potent, full agonist of C5a, but at higher concentrations had a superefficacious effect compared to the natural factor. The maximal efficacy of this analogue was 216 ± 56% that of C5a in stimulating the release of β-glucuronidase from human neutrophils. C5aR activation and binding curves both occurred in the same concentration range with YSFKPMPLaR, characteristics not observed with natural C5a or more conformationally flexible C-terminal agonists. YSFKPMPLaR was then used as a C-terminal effector template onto which was synthesized various C5aR binding determinants from the N-terminal core domain of the natural factor. In general, the presence of N-terminal binding determinants had little effect on either potency or binding affinity when the C-terminal effector region was presented to the C5aR in this biologically active conformation. However, one peptide, C5a12-20-Ahx-YSFKPMPLaR, expressed a 100-fold increase in affinity for the neutrophil C5aR and a 6-fold increase in potency relative to YSFKPMPLaR. These analyses showed that the peptides used in this study have up to 25% of the potency of C5a in human fetal artery and up to 5% of the activity of C5a in the PMN enzyme release assay.Keywords
This publication has 19 references indexed in Scilit:
- Decapeptide agonists of human C5a: the relationship between conformation and neutrophil responseJournal of Medicinal Chemistry, 1995
- The importance of extended conformations and, in particular, the PII conformation for the molecular recognition of peptidesBiopolymers, 1995
- Reversibility of tachyphylaxis to C5a in guinea pig tissues, perfused human placental lobule, and umbilical arteryInflammation, 1994
- Decapeptide Agonists of Human C5a: The Relationship between Conformation and Spasmogenic and Platelet Aggregatory ActivitiesJournal of Medicinal Chemistry, 1994
- Identification of a Receptor-Binding Region in the Core Segment of the Human Anaphylatoxin C5aJournal of Medicinal Chemistry, 1994
- Identification and synthesis of a receptor binding site of human anaphylatoxin C5aJournal of Medicinal Chemistry, 1991
- Autonomous folding and coenzyme binding of the excised pyridoxal 5'-phosphate binding domain of aspartate aminotransferase from Escherichia coliBiochemistry, 1991
- C5a-mediated release of interleukin 6 by human monocytesClinical Immunology and Immunopathology, 1990
- Identification of receptor-binding residues in the inflammatory complement protein C5a by site-directed mutagenesis.Proceedings of the National Academy of Sciences, 1989
- Sterols: Isolation from a Blue-Green AlgaScience, 1968