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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.


a The proposed binding modes for the quinoxaline (yellow carbons) and urea (cyan carbons) series with the influential mutated residues in CXCR2 shown in CPK. The consistent influence of K320 locates the acidic functionality in the antagonists, yet the varying effects of D143 on representatives of these two series suggest that the hydrophobic groups are located differently. b Overlay of the CXCR1 NMR structures from the PDB (code 2LNL) N320 is shown in green CPK and influential mutants from our experiments in purple CPK. The protein backbones, in ribbon representation, are coloured from N (blue) to C (red) termini
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Fig14: a The proposed binding modes for the quinoxaline (yellow carbons) and urea (cyan carbons) series with the influential mutated residues in CXCR2 shown in CPK. The consistent influence of K320 locates the acidic functionality in the antagonists, yet the varying effects of D143 on representatives of these two series suggest that the hydrophobic groups are located differently. b Overlay of the CXCR1 NMR structures from the PDB (code 2LNL) N320 is shown in green CPK and influential mutants from our experiments in purple CPK. The protein backbones, in ribbon representation, are coloured from N (blue) to C (red) termini

Mentions: The mutagenesis experiments that were undertaken did show that residues at the intracellular end of the TM domains had an influence on the binding and/or potency of the antagonists whilst one proposed as critical within the TM domain did not show any influence. However, the expected overlay of the antagonists based upon their ligand-only overlays was not reproduced in the effects seen against the various mutant receptors. The presumed binding modes derived from this work are shown in Fig. 14a. The residues proposed for mutagenesis, and the interpretation of their effects, were very dependent upon the model used to create the homology model for CXCR2 at the time, and so a review of how the latest GPCR crystal structures could have influenced this project was presented.Fig. 14


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)

a The proposed binding modes for the quinoxaline (yellow carbons) and urea (cyan carbons) series with the influential mutated residues in CXCR2 shown in CPK. The consistent influence of K320 locates the acidic functionality in the antagonists, yet the varying effects of D143 on representatives of these two series suggest that the hydrophobic groups are located differently. b Overlay of the CXCR1 NMR structures from the PDB (code 2LNL) N320 is shown in green CPK and influential mutants from our experiments in purple CPK. The protein backbones, in ribbon representation, are coloured from N (blue) to C (red) termini
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig14: a The proposed binding modes for the quinoxaline (yellow carbons) and urea (cyan carbons) series with the influential mutated residues in CXCR2 shown in CPK. The consistent influence of K320 locates the acidic functionality in the antagonists, yet the varying effects of D143 on representatives of these two series suggest that the hydrophobic groups are located differently. b Overlay of the CXCR1 NMR structures from the PDB (code 2LNL) N320 is shown in green CPK and influential mutants from our experiments in purple CPK. The protein backbones, in ribbon representation, are coloured from N (blue) to C (red) termini
Mentions: The mutagenesis experiments that were undertaken did show that residues at the intracellular end of the TM domains had an influence on the binding and/or potency of the antagonists whilst one proposed as critical within the TM domain did not show any influence. However, the expected overlay of the antagonists based upon their ligand-only overlays was not reproduced in the effects seen against the various mutant receptors. The presumed binding modes derived from this work are shown in Fig. 14a. The residues proposed for mutagenesis, and the interpretation of their effects, were very dependent upon the model used to create the homology model for CXCR2 at the time, and so a review of how the latest GPCR crystal structures could have influenced this project was presented.Fig. 14

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.