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

• Published in: The Journal of biological chemistry 2015-08, Vol.290 (32), p.19489-19495
• Main Authors: Jazayeri, Ali, Dias, Joao M., Marshall, Fiona H.
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Allosteric Site - drug effects; Computer-Aided Design; Crystallography, X-Ray - methods; Drug Design; drug discovery; G protein-coupled receptor (GPCR); Humans; Ligands; membrane protein; Minireviews; Models, Molecular; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; X-ray crystallography
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.R115.668251

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.