Structural determinants of unexpected agonist activity in a retro-peptide analogue of the SDF-1a N-terminus

We have synthesized two retro-peptide analogs of the stromal cell derived growth factor 1 (SDF-1a) segment known to be crit. for CXCR4 receptor binding, corresponding to the sequences HSEFFRCPCRFFESH and HSEFFRGGGRFFESH. We have assayed the ability of these peptides to activate extracellular signal-regulated kinase 1/2 phosphorylation in cells over expressing the SDF-1a receptor, finding that the first variant was able to serve as an agonist of CXCR4, whereas the second one was inactive. Finally, by comparing representative soln. structures of the two peptides, we have found that the biol. response of HSEFFRCPCRFFESH may be ascribed to a b-b-type turn motif centered on Phe4-Phe5.