LAUSR

Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate the system pharmacologically. Here, we identified a conserved cluster of three aromatic receptor residues that anchors the second extracellular loop (ECL2) to the top of receptor transmembrane helices (TM) 4 and 5 and enables recognition of both shared and specific characteristics of interacting chemokines. This cluster was essential for the activation of several chemokine receptors. Furthermore, characteristic motifs of the ß1 strand and 30s loop make the two main CC-chemokine subgroups—the macrophage inflammatory proteins (MIPs) and monocyte chemoattractant proteins (MCPs)—differentially dependent on this cluster in the promiscuous receptors CCR1, CCR2, and CCR5. The cluster additionally enabled CCR1 and CCR5 to discriminate between closely related MIPs based on the N terminus of the chemokine. G protein signaling and β-arrestin2 recruitment assays confirmed the importance of the conserved cluster in receptor discrimination of chemokine ligands. This extracellular site may facilitate the development of chemokine-related therapeutics. Description A cluster of aromatic residues in some chemokine receptors creates ligand-specific contact points. A cluster to decipher chemokines Chemokines direct immune cell migration during development, homeostasis, and beneficial as well as pathological inflammation. However, targeting chemokine signaling in a selective manner is challenging, in part, because of the promiscuous pairing of chemokine ligands with multiple receptors. Larsen et al. identified a structure in a group of chemokine receptors that enables them to discriminate between closely related chemokines. A trio of aromatic residues on their extracellular terminus enabled the receptors CCR1, CCR2, and CCR5 to distinguish between chemokine subgroups and specific chemokines in these subgroups through common and unique contact points with the chemokine N terminus. The findings may inform drug development to more selectively modulate chemokine signaling.