This application is to partially fund a junior research position at the Oulu Biocenter (BCO) and the Department of Biochemistry, University of Oulu, concerning structural determination of human adenosine receptor subtype selectivity and allosteric modulation. As a basis of this project, we recently determined the crystal structure of the human adenosine A2A receptor. By the research described in the research plan, we will accomplish one or more of following goals (2010-2014): To solve human adenosine A1, A2A, A2B and A3 structure complexes with subtype-selective ligands and co-factors. To study allosteric modulation of adenosine receptors. To study the functional/structural role of lipids those were co-crystallized in the initial A2A structure. To determine the structure of carboxy terminal domain(s) of human A2A receptor and further characterize its functional properties and interaction partners. To biophysically characterize the dynamic and conformational changes upon ligand/co-factor binding in the purified adenosine receptor those are important to the activation mechanism. The main goal is to establish an independent research team and equipments at the BCO. The team would be specialized on structural and functional studies of GPCRs. The BCO and the protein science facilities available at Oulu University provides excellent environment for the research proposed, with access to instruments and facilities needed for the proposed research. The major collaborators in this project include R.C.Stevens (the Scripps Research Institute, USA) and A. Ijzeman (University of Leiden, Netherlands). We will seek more collaboration nationally and internationally on GPCRs and biophysical characterization of the targets. With this application, partial salary of the PI is applied. The BCO is committed support a start up package for setting up a laboratory, an annual grant for materials and consumables and salary for two other project members for this proposal.
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