GPCR-G Protein Interactions Investigated Using Electron Microscopy and Surface Plasmon Resonance. (360G-Wellcome-089663_Z_09_Z)
G Protein Coupled Receptors (GPCRs} are pharmacologically important membrane receptors comprising, at over BOO proteins, the largest superfamily (1%) of the human genome. They are the first link in a chain of signal transduction events that passes messages from the exterior of the cell to the nucleus, ultimately resulting in transcription and translation of proteins in a response pathway. Initial signals occur via interactions with heterotrimeric guanine nucleotide binding proteins (G proteins} (Figure 1) [1]. G protein activation by the receptor initiates signalling via changes in the levels of intracellular messengers such as cyclic-3',5'-monophosphate (cAMP), Ca2+ or signalling lipids. Classical GPCR signalling theory suggests that the activated ligand-receptor complex is required for G protein binding [2], but more recent evidence has shown that a pre-coupled receptor-G protein complex [3; 4], and even a liganded receptor dimer-G protein complex is able to form [5]. All GPCRs have a canonical structure of seven transmembrane ?-helices. The N-terminus in extracellular, the C-terminus is intracellular, and there are three interhelical loops on either side of the membrane. The GPCR family has proved particularly intractable to most high-resolution structural techniques such as X-ray crystallography or nuclear magnetic resonance (NMR), due to the intrinsic conformal flexibility of these proteins, their relatively low expression levels and the fact that they are membrane-bound. While 30-40 % of current drugs target GPCRs [6], less than 2 % of the Protein Database (PDB) comprises membrane protein structures [7]. GPCR structures make up fewer than 30 of the known membrane protein structures, and of those, approximately two thirds are rhodopsin structures (see Table 1 in [8] and references cited therein}. Many functional and structural aspects of the receptor-G protein complex remain to be elucidated, and mechanistic information about the complex is essential for rapid, targeted drug research to proceed apace.
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Grant Details
Amount Awarded | 152906 |
Applicant Surname | Adamson |
Approval Committee | Molecules, Genes and Cells Funding Committee |
Award Date | 2009-05-29T00:00:00+00:00 |
Financial Year | 2008/09 |
Grant Programme: Title | PhD Studentship (Basic) |
Internal ID | 089663/Z/09/Z |
Lead Applicant | Dr Roslin Adamson |
Partnership Value | 152906 |
Planned Dates: End Date | 2014-01-31T00:00:00+00:00 |
Planned Dates: Start Date | 2009-10-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | South East |
Sponsor(s) | Prof David Stuart |