LAUSR

Structure-function analysis of chemokines and their shared receptor may aid in the development of small-molecule inhibitors. Deciphering chemokine binding Chemokines are small chemoattractant proteins that bind to chemokine receptors, which are members of the family of G protein–coupled receptors (GPCRs), to stimulate the directed migration of immune cells to sites of infection or inflammation. Monocyte chemoattractant proteins (MCPs) are chemokines that stimulate the receptor CCR2, which is found on monocytes and macrophages and is implicated in the pathogenesis of atherosclerosis and type 2 diabetes. Using chimeric MCP proteins and mutated CCR2 receptors, Huma et al. identified the N-terminal region of the chemokine as important for determining both receptor-binding affinity and the efficiency of receptor activation. The authors also showed that a region in the transmembrane domains of CCR2 was a critical site for chemokine-receptor interactions. These data may aid in the development of small-molecule inhibitors to treat diseases in which CCR2 signaling contributes to the pathology. Chemokines and their receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different chemokines can induce distinct responses at the same receptor. In comparison to monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), the chemokines MCP-2 (CCL8) and MCP-3 (CCL7) are partial agonists of their shared receptor CCR2, a key regulator of the trafficking of monocytes and macrophages that contribute to the pathology of atherosclerosis, obesity, and type 2 diabetes. Through experiments with chimeras of MCP-1 and MCP-3, we identified the chemokine amino-terminal region as being the primary determinant of both the binding and signaling selectivity of these two chemokines at CCR2. Analysis of CCR2 mutants showed that the chemokine amino terminus interacts with the major subpocket in the transmembrane helical bundle of CCR2, which is distinct from the interactions of some other chemokines with the minor subpockets of their receptors. These results suggest the major subpocket as a target for the development of small-molecule inhibitors of CCR2.