Mapping the binding of the tail of the CXCR4 receptor n-terminal extracellular to stromal cell-derived factor-1α

The solution structure of monomeric stromal cell-derived factor-1alpha (SDF-1alpha), the natural ligand for the CXCR4 G-coupled receptor, has been solved by multidimensional heteronuclear NMR spectroscopy. The structure has a characteristic chemokine fold and is in excellent agreement with the individual subunits observed in the crystal structures of dimeric SDF-1alpha. Using various peptides derived from. the N-terminal extracellular tail of the CXCR4 receptor, we show that the principal determinants of binding reside in the N-terminal 17 residues of CXCR4, with a major contribution from the first six residues. From N-15/H-1(N) chemical shift pertubation studies we show that the interaction surface on SDF-1alpha is formed by the undersurface parallel beta-sheet bounded by the N-terminal loop of the three-stranded anti on one side and the C-terminal helix on the other. This surface overlaps with but is not identical to that mapped on several other chemokines for the binding of equivalent peptides derived from their respective receptors. Published by Elsevier Ltd.