GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1–2 September 2014
| العنوان: | GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1–2 September 2014 |
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| المؤلفون: | Heifetz, Alexander, Schertler, Gebhard F.X., Seifert, Roland, Tate, Christopher G., Sexton, Patrick M., Gurevich, Vsevolod V., Fourmy, Daniel, Cherezov, Vadim, Marshall, Fiona H., Storer, R.I., Moraes, Isabel, Tikhonova, Irina G., Tautermann, Christofer S., Hunt, Peter, Ceska, Tom, Hodgson, Simon, Bodkin, Mike J., Singh, Shweta, Law, Richard J., Biggin, Philip C. |
| بيانات النشر: | ETH Zurich |
| مصطلحات موضوعية: | T4L, T4-lysozyme, BRIL, apocytochrome b562RIL, HGMP, hierarchical GPCR modelling protocol, TM, trans-membrane helix, SDM, site-directed mutagenesis, ECL, extracellular loop, 5-HT2B and 5-HT2C, human 5-hydroxytryptamine receptors 2B and 2C, respectively, PDB, Protein Data Bank, CRF1, corticotropin releasing factor receptor 1, β2AR, β2-adrenergic receptor, GPCRs, G-protein coupled receptors, GLAS, GPCR-likeness assessment score, α1B Adrenergic receptor, H1, histamine receptor 1, 7TM, seven-transmembrane domain, 3D, three-dimensional, δ-OR, delta-opioid receptor, GLP-1, Glucagon-like peptide-1 receptor, hM3R, human muscarinic M3 receptor, Dopamine D2 receptor, CXCR1, CXCR2, CCR4 and CCR5, chemokine receptors, 3. Good health, ProS, pairwise protein similarity method, MD, molecular dynamic simulations, CCK2R, cholecystokinin receptor-2, XFELs, x-ray free electron lasers |
| الوصف: | 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. Naunyn-Schmiedeberg's archives of pharmacology, 388 (8) ISSN:0028-1298 ISSN:1432-1912 |
| اللغة: | English |
| تدمد: | 0028-1298 1432-1912 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::2173e66f5c24b1f0755c14aa47a50559Test |
| رقم الانضمام: | edsair.doi...........2173e66f5c24b1f0755c14aa47a50559 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00281298 14321912 |
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