Figure 2. CXCL12-CXCR4 PPI and druggable hot spots A.
Hot spots that mediate N-terminal CXCR4 peptide binding to monomeric CXCL12 (L55C/I58C) (PDB ID: 2N55). To the left, tyrosines Y12 and Y21 of CXCR4 N-terminus recognize and bind to potential hot spots on the surface of CXCL12. To the right, isoleucines I4 and I6 of the CXCR4 N-terminus bind to hot spots on the surface of CXCL12 (PDB ID: 2N55). B. FTMap analysis of potentially druggable hot spots on monomeric CXCL12 (L55C/I58C) (PDB ID: 2N55). Probe clusters were sorted based on the number of probes in each cluster (Cluster Strength, CS). To the left, a large probe cluster, CS1 (green, 27 probes), was found at a site near the Y21 binding site and a small probe cluster, CS6 (purple, 6 probes), overlaps with the Y12 binding site. To the right, five probe clusters, CS2 (cyan, 15 probes), CS3 (yellow, 14 probes), CS4 (green, 12 probes), CS5 (grey, 11 probes), and CS7 (blue, 5 probes), were found at sites overlapping with the I4 and I6 binding site and surrounding area. C. Hot spots that mediate sulfated N-terminal CXCR4 peptide binding to CXCL12 (PDB ID: 2K05). Sulfotyrosines sY12 and sY21 of CXCR4 N-terminus recognize and bind to sulfotyrosine-binding sites on the surface of CXCL12 (PDB ID: 2K05, only monomer A depicted). D. FTMap analysis of potentially druggable hot spots on CXCL12 (PDB ID: 2K05, only monomer A used). Probe clusters were sorted based on the number of probes in each cluster (Cluster Strength, CS). Five probe clusters, CS1 (cyan, 25 probes), CS4 (yellow, 13 probes), CS5 (green, 9 probes), CS6 (blue, 5 probes), and CS8 (grey, 3 probes) were found at sites overlapping with the sY12 and sY21-binding sites and surrounding areas. Probe clusters CS2 (purple, 15 probes) and CS3 (yellow, 15 probes) were found at sites that would normally interact with I4 and I6 in the monomeric CXCL12 complex.