G protein-coupled receptors (GPCRs) constitute the largest class of drug targets in the human genome, which highlights the importance of understanding the molecular basis of their activation, downstream signaling, and regulation. Since 2007, great progress has been made in the field of GPCR structure determination and their signaling complexes at the molecular level. Here, we summarize the high-resolution structures of over 30 different GPCRs with their co-crystallized ligands, and outline the successful strategies involved, including construct design, expression systems, and lipidic cubic phase (LCP) composition, and the many key technical parameters of the crystallization methods. By comparing the success rates of different strategies used in the past, we wish to pave the road for more successful structure-function research for GPCRs in the future. Protein-engineering strategies, reviewed here, have accelerated GPCR structure determination.The optimization of GPCR ligands, expression systems, and detergents have allowed for the production of high-quality protein samples in quantities sufficient for crystallization.Crystallization precipitant screen design and LCP host lipids are outlined.Future challenges and research directions are proposed.
- Ligand binding
- Lipidic cubic phase
- Protein engineering
- Structure-based drug discovery
ASJC Scopus subject areas