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UK funding (£480,689): Understanding the functional activation of G protein-coupled receptors (GPCRs) in the context of their lipid bilayer environment Ukri5 Aug 2019 UK Research and Innovation, United Kingdom
Overview
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Understanding the functional activation of G protein-coupled receptors (GPCRs) in the context of their lipid bilayer environment
| Abstract | Human beings are made up of millions of cells. To sustain life these cells need to be able to work together. Each cell has its own machinery and is surrounded by a water-impermeable membrane forming a physical boundary. This membrane consists of a lipid bilayer into which a large number of water-insoluble proteins are embedded, so-called membrane proteins. These are essential for transmitting required nutrients, energy and information across the membrane. To work in a coordinated fashion, cells need to be able to adjust themselves to changes in their surroundings. This requires the ability to communicate environmental variations across the membrane bilayer. A large family of ca. 800 membrane embedded proteins is tasked to do this. These so-called G protein-coupled receptors (GPCRs) have the ability to sense the presence of a wide range of extracellular stimuli in the form of chemicals, peptides and proteins, for example odorants, pheromones, neurotransmitters, hormones, light (amongst others) and to communicate their presence to the cell interior. As cellular sensors, GPCRs are key players in the regulation of a wide range of normal, physiological and disease-related processes. Located on the cell surface they are already targeted by many of the currently available drugs. However, there is vast potential to develop this further in order to tackle many more diseases or improve existing treatments, with the promise to lead to dramatic improvements in health in the future. To achieve this, there is an urgent need to obtain a better understanding of how GPCRs function. Typically this involves obtaining information on these proteins at a molecular level, and chemists and biologists are using a range of sophisticated methodologies that generate such insight. For an increasing number of these GPCRs it has recently become possible to visualize the structural aspects of these highly unstable and difficult to handle proteins in the form of static snapshot pictures. Based on these, one would assume that GPCRs function as simple on/off switches. However, GPCRs are highly mobile, shape-shifting proteins and this trademark characteristic lies at the heart of their function. Accordingly, many questions remain to be answered as the simple on/off picture is gradually replaced by one portraying GPCRs as rheostats i.e. continuous regulators. In our proposal we will investigate the dynamic nature of these receptors using a particular GPCR called b1 adrenergic receptor (b1AR). This receptor plays an important role in the regulation of heart function, is involved in many diseases and is targeted by the famous beta blocker drugs. To understand the role of the dynamic nature for GPCR function we will mimic the natural cellular membrane environment and embed the receptor in small particles that resemble lipid bilayer rafts. We will then use a technique called nuclear magnetic resonance (NMR) spectroscopy to investigate how the shape-shifting properties of these proteins contribute to their function. Using such small membrane bilayer particles will allow us to study b1AR under realistic conditions and to focus on the role of the lipid environment for GPCR function. NMR spectroscopy will give us insight on how this receptor interacts with a range of proteins that couple to the receptor and how the initial signal sensed by the GPCR is transmitted from the cell exterior across the membrane to the inside of the cell. We will be able to study regions of the receptor that for technical reasons are inaccessible to other investigation methods, which is particularly valuable. Our study will improve our understanding of how this receptor works and will create a basis for the development of new drugs. While some of our findings will be specific to the b1AR receptor we are anticipating that many of the discoveries will also advance our general understanding of how GPCRs work. |
| Category | Research Grant |
| Reference | BB/S015892/1 |
| Status | Closed |
| Funded period start | 05/08/2019 |
| Funded period end | 04/08/2022 |
| Funded value | £480,689.00 |
| Source | https://gtr.ukri.org/projects?ref=BB%2FS015892%2F1 |
Participating Organisations
| University of Cambridge | |
| University of Warwick |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: University of Cambridge, Cambridge.
