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

Heifetz A, Schertler GF, Seifert R, Tate CG, Sexton PM, Gurevich VV, Fourmy D, Cherezov V, Marshall FH, Storer RI, Moraes I, Tikhonova IG, Tautermann CS, Hunt P, Ceska T, Hodgson S, Bodkin MJ, Singh S, Law RJ, Biggin PC - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK, Alexander.Heifetz@Evotec.com.

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.

No MeSH data available.


Schematic representation of the CCK2R which can adopt two distinct conformational states upon CCK activation. The CCK2RG state couples to phospholipase-C activation and the CCK2Rβ state recruits β-arrestins. This figure also shows that GV150013X, a competitive antagonist on CCK2RG, is inefficient to inhibit recruitment of β-arrestins by CCK2Rβ because of steric hindrance at the orthosteric binding site
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Fig5: Schematic representation of the CCK2R which can adopt two distinct conformational states upon CCK activation. The CCK2RG state couples to phospholipase-C activation and the CCK2Rβ state recruits β-arrestins. This figure also shows that GV150013X, a competitive antagonist on CCK2RG, is inefficient to inhibit recruitment of β-arrestins by CCK2Rβ because of steric hindrance at the orthosteric binding site

Mentions: The concept of biased signalling has also been explored in the cholecystokinin receptor-2 (CCK2R, which also binds the digestive hormone gastrin) (Magnan et al. 2011, 2013) and is a GPCR for which pharmaceutical companies and academic laboratories have successfully developed non-peptide ligands, mostly antagonists. Since CCK2R is a potential target in several pathologies of the central nervous system (anxiety, panic attacks), of the gut (peptic ulcer disease) and of neuroendocrine cancers, the effects of a series of such ligands on stimulation of phospholipase-C and as well as on recruitment of non-visual arrestins and stimulation of receptor internalisation have been studied (see Fig. 5).Fig. 5


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

Heifetz A, Schertler GF, Seifert R, Tate CG, Sexton PM, Gurevich VV, Fourmy D, Cherezov V, Marshall FH, Storer RI, Moraes I, Tikhonova IG, Tautermann CS, Hunt P, Ceska T, Hodgson S, Bodkin MJ, Singh S, Law RJ, Biggin PC - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

Schematic representation of the CCK2R which can adopt two distinct conformational states upon CCK activation. The CCK2RG state couples to phospholipase-C activation and the CCK2Rβ state recruits β-arrestins. This figure also shows that GV150013X, a competitive antagonist on CCK2RG, is inefficient to inhibit recruitment of β-arrestins by CCK2Rβ because of steric hindrance at the orthosteric binding site
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4495723&req=5

Fig5: Schematic representation of the CCK2R which can adopt two distinct conformational states upon CCK activation. The CCK2RG state couples to phospholipase-C activation and the CCK2Rβ state recruits β-arrestins. This figure also shows that GV150013X, a competitive antagonist on CCK2RG, is inefficient to inhibit recruitment of β-arrestins by CCK2Rβ because of steric hindrance at the orthosteric binding site
Mentions: The concept of biased signalling has also been explored in the cholecystokinin receptor-2 (CCK2R, which also binds the digestive hormone gastrin) (Magnan et al. 2011, 2013) and is a GPCR for which pharmaceutical companies and academic laboratories have successfully developed non-peptide ligands, mostly antagonists. Since CCK2R is a potential target in several pathologies of the central nervous system (anxiety, panic attacks), of the gut (peptic ulcer disease) and of neuroendocrine cancers, the effects of a series of such ligands on stimulation of phospholipase-C and as well as on recruitment of non-visual arrestins and stimulation of receptor internalisation have been studied (see Fig. 5).Fig. 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK, Alexander.Heifetz@Evotec.com.

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.

No MeSH data available.