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

Abstract

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.

Figure 1

Superimposition of the ‘ionic lock’ of the β1AR, β2AR and Adenosine A_2a crystal structures, illustrating that the salt bridge between the key arginine and glutamate residues in the DRY motif linking TM3 to TM6 are broken in each case. The receptors are believed to be in an ‘almost off’ state, but it can be seen that each structure has the glutamate in significantly different positions with respect to one another and further structures are required to rationalize these differences. β₁AR in blue, β₂AR in pink, Adenosine A_2a in green.

Figure 2

Superimposition of crystal structures of cyanopindolol in β1 and carazolol in β2 adrenoceptors (A) illustrating how the shape of the pocket in β1 shown in green (B) differs from the shape of the pocket in β2 shown in blue (C) [β1 green surface also shown in (C)]. These shape differences, coupled with specific amino acid residue changes described in the main text, suggest that more selective agonists and antagonists could be designed for these receptor targets.