G protein-coupled receptors (GPCRs) comprise the largest protein family in human genome. The receptors sense molecules outside the cell and activate inside signal transduction pathways. GPCRs are involved in many human diseases, and represent the target of approximately 40% of all modern medicinal drugs. Structural studies of GPCRs remain enormously challenging.

The G protein-coupled chemokine receptors, CXCR4 and CCR5, are principle co-receptors for HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15, and the crystal structure of CCR5 bound to the marked HIV drug maraviroc. These structures deepen our understanding of the exact molecular details and mechanism of HIV-1 infection, and address specificity issues as well as factors that define viral glycoprotein gp120 binding. The CCR5 structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry by maraviroc. Structural characterization of ligand binding behavior of CXCR4 and CCR5 lays a foundation for carrying out next generation drug discovery aimed at inhibiting viral entry of different HIV-1 strains.

Purinoceptor 12 (P2Y₁₂R) is a major clinical target, which regulates platelet activation and thrombus formation. Recently, we solved three crystal structures of human P2Y₁₂R in complex with its non-nucleotide reversible antagonist AZD1283, with a full agonist 2-methylthio-adenosine-5'-diphosphate (2MeSADP), and with the corresponding ATP derivative (2MeSATP). As the first example of a GPCR where agonist access to the binding pocket requires large scale rearrangements in the highly malleable extracellular region, the structural studies therefore will provide invaluable insight into the pharmacology and mechanisms of action of agonists. The structures reveal details of ligand interactions with the receptor, and points to the existence of at least two non-overlapping ligand binding pockets at its extracellular interface. The structures provide essential insights and a solid 3D platform for the development of improved P2Y₁₂R ligands and allosteric modulators as drug candidates.