NMR studies of active N-terminal peptides of stromal cell-derived factor-1- Structural basis for receptor binding

Stromal cell-derived factor 1 (SDF-1), a member of the CXC chemokine family , is the only chemokine to bind to the receptor CXCR4 This receptor is also a co-receptor for syncytia-inducing forms of HIV in CD4(+) cells. In addit ion, SDF-1. is responsible for attracting mature lymphocytes to the bone ma rrow and can therefore contribute to host versus graft rejection in bone ma rrow transplantation, Clearly, by manipulating SDF-1 activity, we could fin d a possible anti-viral AIDS treatment and aid in bone marrow transplantati on. SDF-1 binds to CXCR4 primarily via the N terminus, which appears flexib le in the recently determined three-dimensional structure of SDF-1. Strikin gly, short N-terminal SDF-1 peptides have been shown to have significant SD F-1 activity, By using NMR, we have determined the major conformation of th e N terminus of SDF-1 in a 17-mer (residues 1-17 of SDF-1) and a g-mer dime r (residues 1-9 of SDF-1 linked by a disulfide bond at residue 9). Residues 5-8 and 11-14 form similar structures that can be characterized as a beta- turn of the beta-alpha R type. These structural motifs are likely to be int erconverting with other states, but the major conformation may be important for recognition in receptor binding. These results suggest for the first t ime that there may be a link between structuring of short N-terminal chemok ine peptides and their ability to activate their receptor. These studies wi ll act as a starting point for synthesizing non-peptide analogs that act as CXCR4 antagonists.