Activation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3

J Biol Chem. 2003 Jan 17;278(3):1892-903. doi: 10.1074/jbc.M205685200. Epub 2002 Oct 30.


CCR5 is a G protein-coupled receptor responding to four natural agonists, the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and monocyte chemotactic protein (MCP)-2, and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have previously identified a structural motif in the second transmembrane helix of CCR5, which plays a crucial role in the mechanism of receptor activation. We now report the specific role of aromatic residues in helices 2 and 3 of CCR5 in this mechanism. Using site-directed mutagenesis and molecular modeling in a combined approach, we demonstrate that a cluster of aromatic residues at the extracellular border of these two helices are involved in chemokine-induced activation. These aromatic residues are involved in interhelical interactions that are key for the conformation of the helices and govern the functional response to chemokines in a ligand-specific manner. We therefore suggest that transmembrane helices 2 and 3 contain important structural elements for the activation mechanism of chemokine receptors, and possibly other related receptors as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Membrane / metabolism
  • Chemokines / metabolism*
  • Ligands
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Receptors, CCR5 / chemistry
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism*
  • Sequence Homology, Amino Acid


  • Chemokines
  • Ligands
  • Receptors, CCR5