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Crystallization and structure determination of adrenergic G protein-coupled receptor subtypes

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3D structure of adrenergic receptors

A European research group is working to obtain the crystal structure of adrenergic receptors. Knowing the three-dimensional structure of the receptor could help in designing drugs to block or activate its function.

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Adrenergic receptors are expressed by various cell types and are central for human physiology. In humans, there are nine subtypes of adrenergic receptors with different functions and pharmacology. Given that adrenergic receptors are important drug targets for treating various conditions, structural studies will help scientists unveil their distinct pharmacological properties. However, the three-dimensional structure of beta 1 and beta 2 receptors has only recently been elucidated. The EU-funded 'Crystallization and structure determination of adrenergic G protein-coupled receptor subtypes' (ADRENERGIC RECEPTORS) project proposes to extend this data and obtain the crystal structure of other beta and alpha adrenergic receptors. To obtain stable receptors suitable for crystallisation procedures, researchers are expressing thermostable mutants or fusing receptors with small soluble proteins. These receptor-expressing constructs are introduced into mammalian or insect cells and the modified receptors are purified using affinity chromatography methods. The ongoing crystallisation experiments are also performed with the addition of antagonist molecules. Subsequent analysis with nuclear magnetic resonance spectroscopy should provide insight into the structural basis of ligand selectivity. Moreover, this enables the study of the dynamic changes in the receptors upon ligand binding. Given the difficulties associated with the crystallisation process, the ADRENERGIC RECEPTORS work constitutes advancement in the technology. In addition, it opens up avenues for using the 3D structure of medically relevant receptors to design effective drugs, hopefully with fewer side-effects.

Keywords

Crystal structure, adrenergic receptors, drug, affinity chromatography, spectroscopy

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