GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014

Alexander Heifetz, Gebhard F X Schertler, Roland Seifert, Christopher G Tate, Patrick M Sexton, Vsevolod V Gurevich, Daniel Fourmy, Vadim Cherezov, Fiona Marshall, R. Ian Storer, Isabel Moraes, Irina Tikhonova, Christofer Tautermann, Peter Hunt, Tom Ceska, Simon Hodgson, Mike Bodkin, Shweta Singh, Richard Law, Philip Biggin

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28 Citations (Scopus)


Abstract G-protein coupled receptors (GPCRs) are the targets of over half of all prescribed drugs today. The UniProt database has records for about 800 proteins classified as GPCRs, but drugs have only been developed against 50 of these. Thus, there is huge potential in terms of the number of targets for new therapies to be designed. Several breakthroughs in GPCRs biased pharmacology, structural biology, modelling and scoring have resulted in a resurgence of interest in GPCRs as drug targets. Therefore, an international conference, sponsored by the Royal Society, with world-renowned researchers from industry and academia was recently held to discuss recent progress and highlight key areas of future research needed to accelerate GPCR drug discovery. Several key points emerged. Firstly, structures for all three major classes of GPCRs have now been solved and there is increasing coverage across the GPCR phylogenetic tree. This is likely to be substantially enhanced with data from x-ray free electron sources as they move beyond proof of concept. Secondly, the concept of biased signalling or functional selectivity is likely to be prevalent in many GPCRs, and this presents exciting new opportunities for selectivity and the control of side effects, especially when combined with increasing data regarding allosteric modulation. Thirdly, there will almost certainly be some GPCRs that will remain difficult targets because they exhibit complex ligand dependencies and have many metastable states rendering them difficult to resolve by crystallographic methods. Subtle effects within the packing of the transmembrane helices are likely to mask and contribute to this aspect, which may play a role in species dependent behaviour. This is particularly important because it has ramifications for how we interpret pre-clinical data. In summary, collaborative efforts between industry and academia have delivered significant progress in terms of structure and understanding of GPCRs and will be essential for resolving problems associated with the more difficult targets in the future.

Original languageEnglish
Article number1111
Pages (from-to)883-903
Number of pages21
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number8
Publication statusPublished - 22 Aug 2015


  • 3D, three-dimensional
  • 5-HT<inf>2B</inf> and 5-HT<inf>2C</inf>, human 5-hydroxytryptamine receptors 2B and 2C, respectively
  • 7TM, seven-transmembrane domain
  • BRIL, apocytochrome b<inf>562</inf>RIL
  • CCK<inf>2</inf>R, cholecystokinin receptor-2
  • CRF1, corticotropin releasing factor receptor 1
  • CXCR<inf>1</inf>, CXCR<inf>2</inf>, CCR<inf>4</inf> and CCR<inf>5</inf>, chemokine receptors
  • Dopamine D<inf>2</inf> receptor
  • ECL, extracellular loop
  • GLAS, GPCR-likeness assessment score
  • GLP-1, Glucagon-like peptide-1 receptor
  • GPCRs, G-protein coupled receptors
  • H<inf>1</inf>, histamine receptor 1
  • HGMP, hierarchical GPCR modelling protocol
  • hM<inf>3</inf>R, human muscarinic M3 receptor
  • MD, molecular dynamic simulations
  • PDB, Protein Data Bank
  • ProS, pairwise protein similarity method
  • SDM, site-directed mutagenesis
  • T4L, T4-lysozyme
  • TM, trans-membrane helix
  • XFELs, x-ray free electron lasers
  • α1B Adrenergic receptor
  • β<inf>2</inf>AR, β<inf>2</inf>-adrenergic receptor
  • δ-OR, delta-opioid receptor

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