The organisational structure of class A GPCRs: Implications for function and drug design

A substantial fraction of therapeutic medicines that are used to treat conditions as wide ranging as heart failure, elevated blood pressure, asthma, and schizophrenia act by either activating or inhibiting members of a family of proteins known as G protein-coupled receptors. These recognise the presence of extracellular hormones and neuro-transmitters and convert this information into signals that allow cells to respond. As well as the members of the G protein-coupled receptor family that are the molecular targets of current medicines, there are many more that are being actively explored to understand the details of their function and their potential roles in the development or modulation of disease. For many years it was considered that G protein-coupled receptors existed and functioned as monomers. However, a wide range of recent studies have indicated that this is probably incorrect and that as well as interacting with themselves to form homo-dimers, different members of the G protein-coupled receptor family that are present in the same cell may interact to form hetero-dimers. This may have important consequences both for understanding the action of currently used drugs and, more importantly, in the manner in which novel therapeutic medicines are identified and developed. The proposal plans to build on the insights my team and I have developed in this area over the past 5 years to understand the molecular basis of how and where G protein-coupled receptor homo-and hetero-dimers form and may be regulated and to take advantage of the identification of a number of hetero-dimer-selective ligands to understand the basis of this selectivity. This is likely to contribute to the development of novel medicines with greater selectivity and more limited side effects.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and the most successfully exploited for the development of therapeutically active, small molecule medicines. All of the currently employed medicines that target GPCRs have been identified and developed based on the presumption that GPCRs exist and function as monomeric species. However, although it has been established that some rhodopsin-family GPCRs can function as monomers, in recent times it has also been established that most, if not all, GPCRs exist in cells as dimers or higher-order complexes. As well as self-associations that generate homo-dimers/oligomers, there is also the potential for interactions between certain pairs of co-expressed GPCRs to generate hetro-dimers/oligomers. As a number of these display distinct regulation and pharmacology, they may represent novel sets of drug targets. A large number of key questions remain, however, before this potential may be realised. This application will employ both current and developing methodologies that require substantial optimisation to explore the quaternary structure of both homo-and hetero-dimers of class A GPCRs at distinct points in their life cycle.
Central points that I will adress include: (1) the molecular basis of alpha1-adrenoceptor homo-dimerisation and the minimum size of the complex, (2) if activation of class A GPCR homo-dimers results in signal generation via ?trans-activation? between the component protomers,(3) the allosteric regulation of GPCR hetero-dimers/oligomers, (4) the pharmacological basis of hetero-dimer/oligomer selective ligands and
(5) the molecular basis and size of GPCR hetero-dimers/oligomers.