Kinetics of CXCL12 binding to atypical chemokine receptor 3 reveal a role for the receptor N terminus in chemokine binding

Ligand-receptor interactions transduce signals intracellularly that induce cellular responses to the ligand. For the atypical chemokine receptor ACKR3, however, it instead binds and sequesters its ligands (chemokines) that it shares with other chemokine receptors, thereby limiting the amount of chemokine available to activate intracellular signaling. Gustavsson et al. discovered the role of the N terminus of ACKR3 in controlling its interaction with the chemokine CXCL12. Binding of the chemokine to the receptor was mediated through its N-terminal region as expected; however, the N terminus of ACKR3 then wrapped around regions of the chemokine to hold it more tightly. These findings have broad implications for understanding chemokine ligand-receptor interactions as well as both chemokine-specific cell biology and drug design.