Mechanisms of chemokine recognition and receptor activation of chemokine receptor CCR7

The chemokine receptor C-C chemokine receptor (CCR7) is essential for immune cell trafficking, cancer metastasis, and autoimmune diseases, making it a significant therapeutic target. This study presents cryo-electron microscopy (cryo-EM) structures of CCR7-Gi complexes bound to CCL19 and CCL21, revealing detailed interactions between the receptor, the two chemokines, and the Gαi protein. Key N-terminal residues and a conserved aromatic patch in the orthosteric pocket are crucial for receptor activation by both ligands, with CCL19 also establishing additional polar interactions that are critical for this process. Mutagenesis studies demonstrate that mutations in these residues result in variable effects on ligand-induced activation, emphasizing the distinct interaction modes of CCL19 and CCL21 with CCR7. Notably, we identify an interesting activation mechanism for CCR7, in which the conventional toggle switch residue W6.48 is replaced by Q6.48, leading to distinctive conformational changes upon ligand binding. These insights enhance our understanding of G-protein-coupled receptor (GPCR) signaling diversity and lay the groundwork for future therapeutic interventions targeting CCR7.