期刊
TRENDS IN BIOCHEMICAL SCIENCES
卷 37, 期 9, 页码 343-352出版社
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tibs.2012.06.003
关键词
G-protein-coupled receptors; GPCR structure; conformational thermostabilisation; thermostability; crystallisation
资金
- Medical Research Council [MRC U105197215]
- MRCT
- Pfizer Global Research
- Wellcome Trust
- BBSRC [BB/G003653/1]
- Heptares Therapeutics
- BBSRC [BB/G003653/1] Funding Source: UKRI
- MRC [MC_U105197215] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G003653/1] Funding Source: researchfish
- Medical Research Council [MC_U105197215] Funding Source: researchfish
G-protein-coupled receptors (GPCRs) are medically important membrane proteins that are targeted by over 30% of small molecule drugs. At the time of writing, 15 unique GPCR structures have been determined, with 77 structures deposited in the PDB database, which offers new opportunities for drug development and for understanding the molecular mechanisms of GPCR activation. Many different factors have contributed to this success, but if there is one single factor that can be singled out as the foundation for producing well-diffracting GPCR crystals, it is the stabilisation of the detergent-solubilised receptor ligand complex. This review will focus predominantly on one of the successful strategies for the stabilisation of GPCRs, namely the thermostabilisation of GPCRs using systematic mutagenesis coupled with thermostability assays. Structures of thermostabilised GPCRs bound to a wide variety of ligands have been determined, which has led to an understanding of ligand specificity; why some ligands act as agonists as opposed to partial or inverse agonists; and the structural basis for receptor activation.
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