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Structural studies of ligand-induced conformational changes in G protein-coupled receptors

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Designing drugs using crystallography

The technically demanding X-ray crystallography method can be used to delineate the three-dimensional structure of molecules. A European research team set out to determine the molecular structure of G-protein coupled receptors (GPCRs).


GPCRs are transmembrane proteins capable of translating ligand binding into a specific cellular response. There are approximately 800 different GPCRs encoded in the human DNA, of which 400 are non-sensory receptors with potential medical relevance. Despite their functional diversity, GPCRs undergo a common conformational change upon stimulation which allows them to interact with different protein partners inside the cell. G proteins are the most prominent GPCR partners and when activated they dissociate into G-α and G-β-γ subunits. In turn, these subunits modulate distinct cellular signalling pathways and cause a change downstream in the cell. The EU-funded 'Structural studies of ligand-induced conformational changes in G protein-coupled receptors' (GPCR CONFORMATIONS) project worked on understanding how different ligands modulate receptor signalling outcome. Researchers focused on the human cannabinoid CB2 receptor and the human vasopressin V2 receptor. CB2 mainly functions in the immune and peripheral nervous systems while V2 is present in the kidneys. Both constitute important drug targets for treating inflammatory diseases, osteoporosis, and diabetes insipidus. The experimental outline entailed the determination of the molecular structure of these receptors when bound to different molecules. In this context, researchers used a series of molecules capable of activating (agonists), suppressing (antagonists) or inversing (inverse agonists) the function of the receptor. Following extensive optimisation of the different crystallisation conditions and techniques, researchers were able to suitably modify and express the V2 and CB2 receptors for X-ray crystallography. Project activities should help shed light on the mechanism of action of these GPCRs. This, in turn, should facilitate the pharmaceutical development of targeted drugs with higher specificity and greater avidity.


Drug, X-ray crystallography, G-protein coupled receptors, cannabinoid CB2 receptor, vasopressin V2 receptor

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