CCR5 is a chemokine receptor that also serves as a co-receptor for HIV-1 gp120 and is essential for HIV-1 entry into some host cells. CCR5 is a class-A G protein–coupled receptor (GPCR) with seven transmembrane segments linked by three extracellular and three intracellular loops. Chemokine ligands bind the N-terminal flexible region of CCR5 and extracellular loop 2, regions that are also involved in HIV-1 gp120 binding. The small-molecule drug maraviroc acts as an allosteric CCR5 inhibitor and has been approved to treat HIV-1 infection. More specifically, maraviroc acts an inverse agonist of CCR5, indicating that the drug stabilizes an inactive conformation of the receptor. Wu and colleagues have now solved the crystal structure of human CCR5 in complex with maraviroc at 2.7-Å resolution, revealing the structural basis for maraviroc's inhibitory properties. In the structure, maraviroc binds a deep pocket formed by residues from six of the receptor's seven transmembrane helices, without contacting the extracellular loops. Although this binding site does not overlap with the major recognition site for chemokine ligands, it involves regions within the transmembrane domain required for CCR5 activation. In fact, CCR5 seems to be held in an inactive conformation in the complex with maraviroc, as implied by two observations. First, two conserved aromatic residues involved in allosteric communication between the ligand pocket and cytoplasmic regions of GPCRs, Trp248 and Tyr244, assume conformations similar to those adopted in the structures of inactive class-A GPCRs. In particular, Trp248 is locked in a hydrophobic interaction with the phenyl group of maraviroc, and this would prevent the residue's movement to an active-state conformation. In addition, helix VI is closely packed with the other helices at the intracellular side, a conformation that would prevent binding of G proteins. Together, these features explain how maraviroc allosterically inhibits chemokine signaling and viral infection. (Science doi:10.1126/science.1241475, 12 September 2013)