Open Access

G protein-coupled receptors: computer-aided ligand discovery and computational structural analyses in the 2010s

In Silico Pharmacology20131:20

DOI: 10.1186/2193-9616-1-20

Received: 6 December 2013

Accepted: 7 December 2013

Published: 20 December 2013


G protein-coupled receptors, or GPCRs, are a large superfamily of proteins found on the plasma membrane of cells. They are involved in most physiological and pathophysiological functions and constitute the target of the majority of marketed drugs. Although these receptors have been historically elusive to attempts of structural determination, GPCR crystallography is now in full blossom, opening the way to structure-based drug discovery and enabling homology modeling. This thematic issue of the journal In Silico Pharmacology, which illustrates how the expanding body of structural knowledge is fostering complex computational analyses of the structure-function relationships of the receptors and their interactions with their ligands, stems from the 31st Camerino-Cyprus-Noordwijkerhout Symposium held in Italy, in May 2013, at the University of Camerino. Specifically, it originates from a session of the symposium entitled “Structure-Based Discovery of Ligands of G Protein-Coupled Receptors: Finally a Reality”, and features a mix of research articles and reviews on the application of computational modeling to the analysis of the structure of GPCRs and the interactions of the receptors with their ligands.


G protein-coupled receptors GPCRs Camerino symposium Water molecules Homology modeling Molecular docking Graph theory

G protein-coupled receptors, or GPCRs, are a large superfamily of proteins found on the plasma membrane of cells, i.e. the membrane that provides the border between the interior of a cell and the extracellular milieu (Pierce et al. 2002). They are the object of the research of the 2012 winners of the Nobel Prize in Chemistry Robert Lefkowitz and Brian Kobilka, who, with their seminal studies, gave a remarkable contribution to the advancement of the body of knowledge surrounding these receptor proteins.

Being located on the plasma membrane, GPCRs are essential components of the mechanism that allows cells to receive signals from their environment and react to them and are involved in most physiological and pathophysiological functions. Hence, they constitute the target of the majority of the targeted drugs. The biological response consequent the interaction of GPCRs with natural ligands or drugs arises from the simultaneous modulation of a variety of signaling pathways. Some of these pathways are mediated by the coupling of the receptors with intracellular heterotrimeric guanine nucleotide binding proteins known as G proteins, hence the name of GPCRs. Moreover, studies pioneered by Robert Lefkowitz demonstrated that alternative GPCR signaling pathways are mediated by the activation of proteins known as arrestins (Pierce et al. 2002; Wisler et al. 2007; Kahsai et al. 2011; Lefkowitz & Shenoy 2005; Martin et al. 2004; Reiter et al. 2012; Rajagopal et al. 2011; Drake et al. 2008; Lefkowitz 2013; Kobilka 2013).

Historically elusive to attempts of structural determination, GPCRs conceded for the first time to the efforts of crystallographers in the year 2000, when Palczewski and coworkers solved for the first time the three-dimentional structure of rhodopsin (Palczewski et al. 2000). Rhodopsin is a peculiar GPCR that, unlike most members of the superfamily, is not activated by diffusible ligands. Conversely, it is a photoreceptor naturally activated by light, which triggers the isomerization of a covalently bound inverse agonist, i.e. a molecule that suppresses the activity of the receptor, into an agonist, i.e. a molecule that activates the receptor (Costanzi et al. 2009). Rhodopsin remained the only GPCR with experimentally elucidated structures until 2007, when the first structures of the β2 adrenergic receptor were solved (Cherezov et al. 2007; Rasmussen et al. 2007; Rosenbaum et al. 2007). Thanks to the introduction of a number of expedients, which include the use of antibodies, fusion proteins, stabilizing mutations and stabilizing ligands, GPCR crystallography is now in full blossom (Stevens et al. 2013; Katritch et al. 2013; Venkatakrishnan et al. 2013; Tate & Schertler 2009; Kruse et al. 2013; Steyaert & Kobilka 2011). At the time of this writing, over 80 structures for over 20 distinct receptors have been solved.

The GPCR structures that are now available are paving the way for structure-based drug discovery, i.e. the rational identification of novel active molecules based on computer-aided analyses of their interactions with their target receptor (Mason et al. 2012; Congreve et al. 2011; Congreve & Marshall 2009; Jacobson & Costanzi 2012; Lane et al. 2013). Moreover, the GPCRs for which crystal structures have been solved provide templates for the construction of models for the remaining members of the superfamily through a technique know as homology modeling and based on the observation that the structures of evolutionarily related proteins, such as GPCRs are, are closely related to each other (Costanzi & Wang 2014; Costanzi 2013; Costanzi 2010; Costanzi 2008).

This thematic issue of the journal In Silico Pharmacology, which illustrates how the expanding body of structural knowledge is fostering complex computational analyses of the structure-function relationships of the receptors and their interactions with their ligands, stems from the 31st Camerino-Cyprus-Noordwijkerhout Symposium held in Italy, in May 2013, at the University of Camerino. Specifically, it originates from a session of the symposium entitled “Structure-Based Discovery of Ligands of G Protein-Coupled Receptors: Finally a Reality”. The issue is opened by an article from Giannella and Angeli, who provide an insightful overview of the evolution of the field of GPCR studies observed from a very special vantage point: the international symposia that are regularly held in Camerino since the late 1970s (Giannella & Angeli 2013). The opening piece is followed by three articles that discuss the implications of the recent advancements in GPCR crystallography for computer-aided ligand discovery: a commentary from Jacobson that illustrates the impact of the solution of GPCR structures on medicinal chemistry efforts for the identification and the development of modulators of pharmaceutically relevant receptors (Jacobson 2013); an article from Mason, Marshall and coworkers that demonstrates how the rational computer-assisted design of GPCR ligands is finally enabled by the availability of GPCR structures as well as the development of techniques that account for the interaction of small molecules with the networks of water molecules and lipophilic hotspots that characterize their target receptors (Mason et al. 2013); an article from Dal Ben, Volpini and coworkers that illustrates how molecular docking targeting GPCR homology models derived from the crystal structures of closely receptors can be applied to the rationalization of structure-activity relationships, thus setting the stage for drug design (Dal Ben et al. 2013). The special issue is closed by two articles that describe computational analyses enabled by the availability of GPCR structures. The first one is an article from Floris, Moro and coworkers, which describes the development of a tool that, given a ligand of interest, facilitates the selection of the most suitable crystal structure for the study of the interactions of the crystallized receptor with that ligand or for the construction of a homology model of different receptor and the study of its interactions with that ligand (Floris et al. 2013). The authors implemented the tool in “Adenosiland”, a web-based platform dedicated to GPCRs activated by the nucleoside adenosine. The second one is an article from Sheftel, Costanzi and coworkers, which describes how the structure of GPCRs can be analyzed through graph theory techniques to highlight their structural features (Sheftel et al. 2013).



This research was supported by funding from American University.

Authors’ Affiliations

Department of Chemistry and Center for Behavioral Neuroscience, American University


  1. Cherezov V, Rosenbaum D, Hanson M, Rasmussen S, Thian F, Kobilka T, Choi H, Kuhn P, Weis W, Kobilka B, Stevens R: High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 2007, 318: 1258–1265. 10.1126/science.1150577PubMed CentralView ArticlePubMedGoogle Scholar
  2. Congreve M, Marshall F: The impact of GPCR structures on pharmacology and structure-based drug design. Br J Pharmacol 2009, 159: 986–996.PubMed CentralView ArticlePubMedGoogle Scholar
  3. Congreve M, Langmead CJ, Mason JS, Marshall FH: Progress in structure based drug design for G protein-coupled receptors. J Med Chem 2011, 54: 4283–4311. 10.1021/jm200371qPubMed CentralView ArticlePubMedGoogle Scholar
  4. Costanzi S: On the applicability of GPCR homology models to computer-aided drug discovery: a comparison between in silico and crystal structures of the beta2-adrenergic receptor. J Med Chem 2008, 51: 2907–2914. 10.1021/jm800044kPubMed CentralView ArticlePubMedGoogle Scholar
  5. Costanzi S: Modeling G protein-coupled receptors: a concrete possibility. Chim Oggi 2010, 28: 26–31.PubMed CentralPubMedGoogle Scholar
  6. Costanzi S: Modeling G protein-coupled receptors and their interactions with ligands. Curr Opin Struct Biol 2013, 23: 185–190. 10.1016/ ArticlePubMedGoogle Scholar
  7. Costanzi S, Wang K: The GPCR crystallography boom: providing an invaluable source of structural information and expanding the scope of homology modeling. Adv Exp Med Biol 2014, 796: 3–13. 10.1007/978-94-007-7423-0_1View ArticlePubMedGoogle Scholar
  8. Costanzi S, Siegel J, Tikhonova I, Jacobson K: Rhodopsin and the others: a historical perspective on structural studies of G protein-coupled receptors. Curr Pharm Des 2009, 15: 3994–4002. 10.2174/138161209789824795PubMed CentralView ArticlePubMedGoogle Scholar
  9. Dal Ben D, Buccioni M, Lambertucci C, Thomas A, Volpini R: Simulation and comparative analysis of binding modes of nucleoside and non- nucleoside agonists at the adenosine A 2B receptor. In Silico Pharmacol 2013, 1: 24. 10.1186/2193-9616-1-24PubMed CentralView ArticlePubMedGoogle Scholar
  10. Drake MT, Violin JD, Whalen EJ, Wisler JW, Shenoy SK, Lefkowitz RJ: beta-arrestin-biased agonism at the beta2-adrenergic receptor. J Biol Chem 2008, 283: 5669–5676.View ArticlePubMedGoogle Scholar
  11. Floris M, Sabbadin D, Ciancetta A, Medda R, Cuzzolin A, Moro S: Implementing the “Best Template Searching” tool into Adenosiland platform. In Silico Pharmacol 2013, 1: 25. 10.1186/2193-9616-1-25PubMed CentralView ArticlePubMedGoogle Scholar
  12. Giannella M, Angeli P: The Camerino symposium series (1978–2013): a privileged observatory of receptorology development. In Silico Pharmacol 2013, 1: 21. 10.1186/2193-9616-1-21PubMed CentralView ArticlePubMedGoogle Scholar
  13. Jacobson K: Crystal structures of the A 2A adenosine receptor and their use in medicinal chemistry. In Silico Pharmacol 2013, 1: 22. 10.1186/2193-9616-1-22PubMed CentralView ArticlePubMedGoogle Scholar
  14. Jacobson KA, Costanzi S: New insights for drug design from the x-ray crystallographic structures of g-protein-coupled receptors. Mol Pharmacol 2012, 82: 361–371. 10.1124/mol.112.079335PubMed CentralView ArticlePubMedGoogle Scholar
  15. Kahsai AW, Xiao K, Rajagopal S, Ahn S, Shukla AK, Sun J, Oas TG, Lefkowitz RJ: Multiple ligand-specific conformations of the beta2-adrenergic receptor. Nat Chem Biol 2011, 7: 692–700. 10.1038/nchembio.634PubMed CentralView ArticlePubMedGoogle Scholar
  16. Katritch V, Cherezov V, Stevens RC: Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol 2013, 53: 531–556. 10.1146/annurev-pharmtox-032112-135923PubMed CentralView ArticlePubMedGoogle Scholar
  17. Kobilka B: The structural basis of g-protein-coupled receptor signaling (nobel lecture). Angew Chem Int Ed Engl 2013, 52: 6380–6388. 10.1002/anie.201302116PubMed CentralView ArticlePubMedGoogle Scholar
  18. Kruse AC, Manglik A, Kobilka BK, Weis WI: Applications of molecular replacement to G protein-coupled receptors. Acta Crystallogr D Biol Crystallogr 2013, 69: 2287–2292. 10.1107/S090744491301322XPubMed CentralView ArticlePubMedGoogle Scholar
  19. Lane JR, Chubukov P, Liu W, Canals M, Cherezov V, Abagyan R, Stevens RC, Katritch V: Structure-based ligand discovery targeting orthosteric and allosteric pockets of dopamine receptors. Mol Pharmacol 2013, 84: 794–807. 10.1124/mol.113.088054PubMed CentralView ArticlePubMedGoogle Scholar
  20. Lefkowitz RJ: A brief history of g-protein coupled receptors (nobel lecture). Angew Chem Int Ed Engl 2013, 52: 6366–6378. 10.1002/anie.201301924View ArticlePubMedGoogle Scholar
  21. Lefkowitz R, Shenoy S: Transduction of receptor signals by beta-arrestins. Science 2005, 308: 512–517. 10.1126/science.1109237View ArticlePubMedGoogle Scholar
  22. Martin NP, Whalen EJ, Zamah MA, Pierce KL, Lefkowitz RJ: PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs/Gi switching. Cell Signal 2004, 16: 1397–1403. 10.1016/j.cellsig.2004.05.002View ArticlePubMedGoogle Scholar
  23. Mason JS, Bortolato A, Congreve M, Marshall FH: New insights from structural biology into the druggability of G protein-coupled receptors. Trends Pharmacol Sci 2012, 33: 249–260. 10.1016/ ArticlePubMedGoogle Scholar
  24. Mason J, Bortolato A, Weiss D, Deflorian F, Tehan B, Marshall F: High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks. In Silico Pharmacol 2013, 1: 23. 10.1186/2193-9616-1-23View ArticleGoogle Scholar
  25. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M: Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000, 289: 739–745. 10.1126/science.289.5480.739View ArticlePubMedGoogle Scholar
  26. Pierce K, Premont R, Lefkowitz R: Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002, 3: 639–650. 10.1038/nrm908View ArticlePubMedGoogle Scholar
  27. Rajagopal S, Ahn S, Rominger DH, Gowen-McDonald W, Lam CM, Dewire SM, Violin JD, Lefkowitz RJ: Quantifying Ligand Bias at Seven-Transmembrane Receptors. Mol Pharmacol 2011, 80: 367–377. 10.1124/mol.111.072801PubMed CentralView ArticlePubMedGoogle Scholar
  28. Rasmussen S, Choi H, Rosenbaum D, Kobilka T, Thian F, Edwards P, Burghammer M, Ratnala V, Sanishvili R, Fischetti R, Schertler G, Weis W, Kobilka B: Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 2007, 450: 383–387. 10.1038/nature06325View ArticlePubMedGoogle Scholar
  29. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ: Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 2012, 52: 179–197. 10.1146/annurev.pharmtox.010909.105800PubMed CentralView ArticlePubMedGoogle Scholar
  30. Rosenbaum D, Cherezov V, Hanson M, Rasmussen S, Thian F, Kobilka T, Choi H, Yao X, Weis W, Stevens R, Kobilka B: GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 2007, 318: 1266–1273. 10.1126/science.1150609View ArticlePubMedGoogle Scholar
  31. Sheftel S, Muratore KE, Black M, Costanzi S: Graph analysis of β 2 adrenergic receptor structures: a “social network” of GPCR residues. In Silico Pharmacol 2013, 1: 16. 10.1186/2193-9616-1-16PubMed CentralView ArticlePubMedGoogle Scholar
  32. Stevens RC, Cherezov V, Katritch V, Abagyan R, Kuhn P, Rosen H, Wuthrich K: The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov 2013, 12: 25–34.PubMed CentralView ArticlePubMedGoogle Scholar
  33. Steyaert J, Kobilka BK: Nanobody stabilization of G protein-coupled receptor conformational states. Curr Opin Struct Biol 2011, 21: 567–572. 10.1016/ CentralView ArticlePubMedGoogle Scholar
  34. Tate CG, Schertler GF: Engineering G protein-coupled receptors to facilitate their structure determination. Curr Opin Struct Biol 2009, 19: 386–395. 10.1016/ ArticlePubMedGoogle Scholar
  35. Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM: Molecular signatures of G-protein-coupled receptors. Nature 2013, 494: 185–194. 10.1038/nature11896View ArticlePubMedGoogle Scholar
  36. Wisler JW, DeWire SM, Whalen EJ, Violin JD, Drake MT, Ahn S, Shenoy SK, Lefkowitz RJ: A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci USA 2007, 104: 16657–16662. 10.1073/pnas.0707936104PubMed CentralView ArticlePubMedGoogle Scholar


© Costanzi; licensee Springer. 2013

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