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

Cédric Govaerts, Antoine Bondue, Jean Yves Springael, Mireia Olivella, Xavier Deupi, Emmanuel Le Poul, Shoshana J. Wodak, Marc Parmentier, Leonardo Pardo, Cédric Blanpain

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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)-1α, MIP-1β, 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.
Original languageEnglish
Pages (from-to)1892-1903
JournalJournal of Biological Chemistry
Publication statusPublished - 17 Jan 2003


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