Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical for chemokine binding and signal transduction

The CC chemokine receptor CCR5 is the receptor for several chemokines and c oreceptor for the entry of HIV-1. Whereas many studies focus on CCR5 intera ction with HIV-1, residues in CCR5 important for chemokine binding and subs equent signal transduction remain poorly understood. Here we use an approac h combining protein structure modeling and site-directed mutagenesis to pro be the structure of CCR5 and its interactions with chemokine ligands and HI V-1. Structural models of CCR5 rationalize extensive biological data about the role of CCR5 in HIV-1 envelope glycoprotein gp120 binding and HIV-1 ent ry. Furthermore, we carry out site-directed mutagenesis guided by structura l analysis of the complex of CCR5 and a chemokine. This leads to the novel observation that certain residues, such as Tyr10 and Lys26, in the N termin us of CCR5 play a critical structural role for ligand binding and signaling . Single glycine substitution of these residues significantly decreases che mokine binding and signal transduction. These results provide new insight i nto the structural basis for CCR5 receptor-ligand interaction and may guide the design of novel inhibitors.