Figure 1.

Selectivity in the chemokine network between CC and CXC chemokines. A, the chemokine network is illustrated with chemokine receptors labeled inside the membrane and the chemokines that bind that receptor labeled outside. The inner phylogenetic tree describes the evolutionary relationships between chemokine receptors. Colors represent each chemokine family: CC (blue), CXC (green), CX3C (red), XC (orange), and atypical (purple). B, the CXC receptors are shown linked with the X residues of their cognate ligands. Each one-letter code is colored by amino acid property: hydrophilic (green), hydrophobic (pink), positive charge (blue), conformationally special (purple), aromatic (yellow), or negative charge (red). The 17 CXC chemokines are represented below the corresponding X residue. C, unique solution-state NMR structures of CXC chemokines were analyzed to determine intramolecular contacts with the side chain of the X residue. These data are illustrated on the structure of CXCL12 (PDB entry 2KED). D, the average lengths of the β1- and β2-strands are shorter in CC chemokines than CXC chemokines, as calculated from 27 solution-state NMR structures. This is demonstrated by structures of CXCL12 (PDB entry 2KED) and CCL20 (PDB entry 2JYO). The X residue in CXCL12 (Pro-10) makes contacts with Leu-29, Thr-31, and Gln-37 to extend secondary structure into the 30s loop. E, each conformer in CC and CXC NMR structures were separated and aligned via the conserved chemokine core. Vectors describing the N terminus of each structure were averaged by family to construct the CC or CXC mean axes, which are separated by 45°. F, the structure of vMIP-II bound to CXCR4 (PDB entry 4RWS) is overlaid with the coordinate system of D. The CXC mean axis is near the N terminus of vMIP-II in the orthosteric pocket, whereas the CC mean axis is outside of the receptor.