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 addition, SDF-1 is responsible for attracting mature lymphocytes to the bone marrow and can therefore contribute to host versus graft rejection in bone marrow transplantation. Clearly, by manipulating SDF-1 activity, we could find a possible anti-viral AIDS treatment and aid in bone marrow transplantation. SDF-1 binds to CXCR4 primarily via the N terminus, which appears flexible in the recently determined three-dimensional structure of SDF-1. Strikingly, short N-terminal SDF-1 peptides have been shown to have significant SDF-1 activity. By using NMR, we have determined the major conformation of the N terminus of SDF-1 in a 17-mer (residues 1-17 of SDF-1) and a 9-mer dimer (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-alphaR type. These structural motifs are likely to be interconverting with other states, but the major conformation may be important for recognition in receptor binding. These results suggest for the first time that there may be a link between structuring of short N-terminal chemokine peptides and their ability to activate their receptor. These studies will act as a starting point for synthesizing non-peptide analogs that act as CXCR4 antagonists.
Elisseeva
E L
EL
Protein Engineering Network of Centers of Excellence and the Department of Biochemistry, 713 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Slupsky
C M
CM
Crump
M P
MP
Clark-Lewis
I
I
Sykes
B D
BD
D000595:Amino Acid Sequence; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism*
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011956:Receptors, Cell Surface