Human 5'-NT und P2X receptors: Structure, function and inhibitor design

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In addition to its major role as a cellular energy carrier, ATP also has an important function as an extracellular signaling substance. In these purinergic signaling pathways, ATP binds to P2X or P2Y receptors. The signaling action is terminated by nucleotidases, which stepwise dephosphorylate ATP to adenosine. Within this project spatial structures of human P2X receptors and of the enzyme ecto-5 -nucleotidase (E-5 -NT) shall be determined by X-ray crystallography. Via these structural studies we aim to characterize the molecular mechanism of the enzyme and the receptors and to contribute to a rational design of specific inhibitors. For human 5 -NT single crystals have been grown, that are suitable for structure determination. The structural studies of P2X receptors shall be achieved via expression, purification and crystallization of the ectodomains of the receptors. The recently determined first X-ray structure of full-length P2X4 from zebrafish shows that the large ATP-binding ectodomain is involved in intensive contacts in the homotrimeric receptor. The structure suggests that the ectodomain alone is stable as a trimer und that it is suitable to study ATP binding and especially the binding of pharmacologically relevant agonists and antagonists.