Structure-Guided Design of Selective Epac1 and Epac2 Agonists
Frank Schwede, Daniela Bertinetti, Carianne N. Langerijs, Michael A. Hadders, Hans Wienk, Johanne H. Ellenbroek, Eelco J. P. de Koning, Johannes L. Bos, Friedrich W. Herberg, Hans-Gottfried Genieser, Richard A. J. Janssen, Holger Rehmann
cAMP is a small molecule produced by cells that activates proteins involved in a wide range of biological processes, including olfaction, pacemaker activity, regulation of gene expression, insulin secretion, and many others. In the case of insulin secretion, cAMP seems to impinge on different stages of the signalling cascade to regulate secretory activity in pancreatic β-cells. Here we have developed a chemically modified version of cAMP that specifically only activates Epac2, one of the cAMP-responsive proteins in this cascade. Furthermore, our cAMP analogue activates Epac2 more potently than cAMP itself does. We have determined several crystal structures of Epac2 in complex with cAMP analogues to help us explain the molecular basis of the observed selectivity and the strong activation potential. In addition, we were able to show that the analogue is able to potentiate glucose-induced secretion of insulin from human pancreatic islets. The principal challenge during this study was identifying and understanding small differences in the cAMP-binding domains of cAMP-regulated proteins and matching these differences with suitable modifications of the cAMP molecule
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