Methodological advances in X-ray crystallography have made possible the recent solution of X-ray structures of pharmaceutically important G protein-coupled receptors (GPCRs), including receptors for biogenic amines, peptides, a nucleoside and a sphingolipid. These high-resolution structures have greatly increased our understanding of ligand recognition and receptor activation. Conformational changes associated with activation common to several receptors entail outward movements of the intracellular side of transmembrane helix 6 (TM6) and movements of TM5 toward TM6. Movements associated with specific agonists or receptors have also been described, e.g. extracellular loop 3 (EL3) in the A(2A) adenosine receptor. The binding sites of different receptors partly overlap but differ significantly in ligand orientation, depth and breadth of contact areas in TM regions, and the involvement of the ELs. A current challenge is how to utilize this structural information for the rational design of novel potent and selective ligands. For example, new chemotypes were discovered as antagonists of various GPCRs by subjecting chemical libraries to in silico docking in the X-ray structures. The vast majority of GPCR structures and their ligand complexes are still unsolved, and no structures are known outside of Family A GPCRs. Molecular modeling, informed by supporting information from site-directed mutagenesis and structure activity relationships, has been validated as a useful tool to extend structural insights to related GPCRs and to analyze docking of other ligands in already crystallized GPCRs.
This study is published online in Molecular Pharmacology and is free to access.