Figure 6.

Differential contribution of chemokine N‐terminal features to interactions with CXCR3/CXCR4 and ACKR3 and distribution between receptor active/inactive states. (A) The entire chemokine N‐terminal region (green) is critical for the binding and activation of the canonical receptors CXCR3 and CXCR4, whereas the most N‐terminal residues (red) as well as the N‐loop (red) do not appear important for activation of the atypical receptor ACKR3. (B) Comparison of the distribution of active (R* green) and inactive (R* red) conformations of CXCR4/CXCR3 and ACKR3 stabilized by ligands (L) targeting the receptor transmembrane ligand‐binding pocket (CRS2). CXCR4 and CXCR3 have low basal activity (light red) and are ‘balanced’ receptors as ligand binding to CRS2 can stabilize either the active state (green) or inactive state (red). ACKR3 is an ‘activation‐prone’ receptor as ligand binding preferentially stabilizes the active state (green) of the receptor leading to β‐arrestin‐2 recruitment. Indeed, so far, no ligand targeting the transmembrane pocket of ACKR3 without displaying agonist activity has been reported.