The impact of GPCR structures on pharmacology and structure-based drug design

Br J Pharmacol. 2010 Mar;159(5):986-96. doi: 10.1111/j.1476-5381.2009.00476.x. Epub 2009 Nov 13.


After many years of effort, recent technical breakthroughs have enabled the X-ray crystal structures of three G-protein-coupled receptors (GPCRs) (beta1 and beta2 adrenergic and adenosine A(2a)) to be solved in addition to rhodopsin. GPCRs, like other membrane proteins, have lagged behind soluble drug targets such as kinases and proteases in the number of structures available and the level of understanding of these targets and their interaction with drugs. The availability of increasing numbers of structures of GPCRs is set to greatly increase our understanding of some of the key issues in GPCR biology. In particular, what constitutes the different receptor conformations that are involved in signalling and the molecular changes which occur upon receptor activation. How future GPCR structures might alter our views on areas such as agonist-directed signalling and allosteric regulation as well as dimerization is discussed. Knowledge of crystal structures in complex with small molecules will enable techniques in drug discovery and design, which have previously only been applied to soluble targets, to now be used for GPCR targets. These methods include structure-based drug design, virtual screening and fragment screening. This review considers how these methods have been used to address problems in drug discovery for kinase and protease targets and therefore how such methods are likely to impact GPCR drug discovery in the future.

Publication types

  • Review

MeSH terms

  • Crystallography, X-Ray
  • Drug Delivery Systems
  • Drug Design*
  • Drug Discovery
  • Humans
  • Protein Conformation*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / drug effects
  • Signal Transduction / drug effects


  • Receptors, G-Protein-Coupled