From G Protein-coupled Receptor Structure Resolution to Rational Drug Design

Abstract

A number of recent technical solutions have led to significant advances in G protein-coupled receptor (GPCR) structural biology. Apart from a detailed mechanistic view of receptor activation, the new structures have revealed novel ligand binding sites. Together, these insights provide avenues for rational drug design to modulate the activities of these important drug targets. The application of structural data to GPCR drug discovery ushers in an exciting era with the potential to improve existing drugs and discover new ones. In this review, we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient findings from structures that are relevant to drug discovery. Finally, we outline some of the approaches used in GPCR structure based drug design.

Keywords: G protein-coupled receptor (GPCR); X-ray crystallography; drug design; drug discovery; membrane protein.

FIGURE 1.

Surface representation of the extracellular face of P2Y₁₂ and PAR1 receptors in complex with the indicated ligands. Receptors are depicted in rainbow spectrum starting with TM1 in blue and ending with TM7 in red. In the P2Y₁₂ receptor, pocket 1 is formed between TM3 and TM7, whereas pocket 2 is formed between TM1–3 and TM7. P2Y₁₂ structure with 2MeSADP shows closed lid conformation. For clarity, portions of the extracellular loops have been removed in the PAR1 structure.

FIGURE 2.

Surface representation of GPR40, β₂-adrenergic receptor and S1P1 receptor in complex with the indicated ligands. The top panel shows the extracellular faces of the receptors; in contrast to the β₂-adrenergic receptor, the route to the ligand binding site GPR40 and S1P1 is occluded from top. The bottom panel shows the side view of the GPR40 and S1P1 receptors where the ligand binding site is clearly visible. It is thought that in these receptors with lipophilic ligands, the route to ligand binding is through the membrane bilayer.