Crystal structures of beta1 and beta2 adrenergic G protein-coupled receptors (GPCRs) have been determined recently. We propose to extend the structural information about this physiologically and medically important GPCR subfamily by obtaining the structures of the beta3 and the alpha adrenergic receptors. The ample experience in GPCR structural biology of the host laboratory, complemented by its multidisciplinary approach, provides an ideal environment for this challenging task. We will make use of high-throughput facilities and methods to optimize the receptor constructs for expression and protein stability. We will use various crystallization methods and available robotic nano-liter dispensers to determine suitable conditions for crystal growth. We will have access to state-of-the-art microcrystallography beamlines at the Swiss Light Source synchrotron at Paul Scherrer Institut (PSI) to test a large number of obtained crystals and collect the best possible diffraction datasets. Once diffraction data of sufficient quality has been obtained, the structure will be solved by molecular replacement. In collaboration with other PSI scientists and external academic and industrial partners we will use the structural results obtained for the adrenergic receptor subtypes to study the structural basis of ligand efficacy, i.e. how the process of ligand binding is translated into receptor function, and to find applications in therapeutic drug development.
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