Two new papers on G protein-coupled receptor (GPCR) structure shed new light on how different ligands interact with their cognate GPCRs. The study by Tan et al. determined the crystal structure of a stabilized CCR5 chemokine receptor — which acts as a co-receptor for HIV-1 viral entry — bound to the HIV drug maraviroc. A comparison of CCR5 with the crystal structure of the chemokine receptor CXCR4 bound to an antagonist suggested that different charge distributions and steric hindrances caused by different residue substitutions determine HIV-1 co-receptor selectivity. For example, maraviroc penetrated deeply into an open binding pocket, whereas the CXCR4 inhibitor inserted less deeply into a more closed binding pocket. The authors note that these insights could aid HIV-1 structure-based drug discovery. The study by Ring et al. determined the first crystal structure of an active state GPCR bound to its native ligand. The structure of the adrenaline-bound, nanobody-stabilized human β2-adrenergic receptor, as well as the receptor bound to other agonists, showed that the adrenaline-bound structure is similar to that bound to other ligands (despite diverse chemical structures with different affinities), but substantial rearrangements occur in extracellular loop 3 and the extracellular tip of transmembrane helix 6. The authors note that these results offer new insight into how diverse agonists can activate a specific GPCR.