Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5

Abstract

The chemokine receptor CCR5 plays a vital role in immune surveillance and inflammation. However, molecular details that govern its endogenous chemokine recognition and receptor activation remain elusive. Here we report three cryo-electron microscopy structures of G_i1 protein-coupled CCR5 in a ligand-free state and in complex with the chemokine MIP-1α or RANTES, as well as the crystal structure of MIP-1α-bound CCR5. These structures reveal distinct binding modes of the two chemokines and a specific accommodate pattern of the chemokine for the distal N terminus of CCR5. Together with functional data, the structures demonstrate that chemokine-induced rearrangement of toggle switch and plasticity of the receptor extracellular region are critical for receptor activation, while a conserved tryptophan residue in helix II acts as a trigger of receptor constitutive activation.

The chemokine receptor CCR5 plays multiple roles in the immune system. Here, structures of G_i1 protein-coupled CCR5 with or without a chemokine bound and of the CCR5- chemokine MIP-1 α complex offer insight into the distinct binding modes of the ligands and into the mechanism of CCR5 activation.