Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex

Abstract

The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom-resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor-gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

Fig. 1

Overall fold of the CCR5/Maraviroc complex and comparison with CXCR4. (A) Overall structure of the two CCR5-rubredoxin molecules related by pseudo-translational symmetry in one ASU. The receptor is colored blue, and the rubredoxin is light-cyan. The ligand Maraviroc is shown in orange sphere representation. The disulfide bonds are shown as yellow sticks. Zinc ions are shown as grey spheres. (B–D) Structure comparison between CCR5 (blue) and CXCR4 (PDB ID: 3ODU, green). The ligands are shown in stick representation. Maraviroc in CCR5 and IT1t in CXCR4 have orange and magenta carbons, respectively. C, top view of the extracellular side of CCR5 and CXCR4; D, bottom view of the intracellular side of CCR5 and CXCR4.

Fig. 2

CCR5 ligand binding pocket for Maraviroc. (A) Key residues in CCR5 for Maraviroc binding. Maraviroc (orange carbons) and receptor residues (blue carbons) involved in ligand binding are shown in stick representation. Other elements are colored as follows: oxygen, red; nitrogen, dark blue; sulfur, yellow; fluorine, light-cyan. The water molecule involved in interacting with Maraviroc is shown as a red sphere. (B) Schematic representation of interactions between CCR5 and Maraviroc. Mutations reported to be critical for Maraviroc binding are indicated with blue squares (11, 16).

Fig. 3

Comparison of the ligand binding pockets between CCR5/Maraviroc and CXCR4/IT1t. (A, D) Top views of the ligand binding pockets in CCR5 (A, blue) and CXCR4 (D, green), showing a more open ligand binding pocket in CCR5. The receptors are shown in both cartoon and molecular surface representations. The ligands are shown in stick representation. Maraviroc in CCR5 and IT1t in CXCR4 have orange and magenta carbons, respectively. (B, E) Side views of the ligand binding pockets in CCR5 (B) and CXCR4 (E), showing that Maraviroc binds deeper in CCR5 than IT1t in CXCR4. (C, F) Top views of the ligand binding pockets in CCR5 (C) and CXCR4 (F). Both CCR5 and CXCR4 surfaces are colored according to their electrostatic potential from red (negative) to blue (positive), showing different charge distribution within the ligand binding pockets of these two receptors.