"GPCRs are involved in a variety of biological and pathological processes ranging from metabolic, neurological and immune system disorders to inflammation. The members of this large family of proteins can be activated by various stimuli including hormones, neurotransmitters, ions, odorants and light. The location of GPCRs on the cell surface and their roles as initiators in many cellular signaling pathways make them predominant drug targets. Around 30% of all drugs on the current therapeutic market function by modulating the activity of GPCRs. One of the most important topics in GPCR field is “biased agonism”: how different ligands induce or stabilise specific conformations of the receptor with distinct pharmacological activity. Equally important is understanding of the basis for ligand selectivity in classes of receptors with identical binding pockets. This selectivity is likely to be determined by the dynamic properties of the pocket or of the ligand entry channel.
NMR spectroscopy can offer structural, dynamic and functional information at atomic resolution into molecular mechanisms of ligand recognition, biased agonism and receptor activation. The aim of the proposed research is to characterise ligand-induced conformational changes in GPCRs and the project will focus on the cannabinoid receptor (CB2), involved in immune response and sensing pain, and is overexpressed in some brain tumors. In particular, I propose a) to label CB2 for NMR analysis based on the successful mutagenesis strategy developed in the host laboratory to produce stabilised recombinant receptors for X-ray crystallography; b) to obtain a dynamic view of the conformational changes in CB2 induced by ligand binding; c) to compare the conformational changes causes by a spectrum of ligands with different activities, from antagonists to agonists.
In addition, this general approach could also be extended to other “difficult” membrane proteins."
Field of science
- /natural sciences/chemical sciences/analytical chemistry/spectroscopy
- /medical and health sciences/health sciences/public and environmental health/epidemics prevention/immunisation
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
- /medical and health sciences/basic medicine/immunology
Call for proposal
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