1. Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
2. Centro de Investigaciones Biológicas (CIB), Spanish National Research Council (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
3. Department of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
4. BIOLOG Life Science Institute, Flughafendamm 9a, 28199 Bremen, Germany

Correspondence to: Holger Rehmann¹ Correspondence and requests for materials should be addressed to H.R. (Email: h.rehmann@UMCutrecht.nl).

Abstract

Epac proteins are activated by binding of the second messenger cAMP and then act as guanine nucleotide exchange factors for Rap proteins^{1, 2}. The Epac proteins are involved in the regulation of cell adhesion³ and insulin secretion⁴. Here we have determined the structure of Epac2 in complex with a cAMP analogue (Sp-cAMPS) and RAP1B by X-ray crystallography and single particle electron microscopy. The structure represents the cAMP activated state of the Epac2 protein with the RAP1B protein trapped in the course of the exchange reaction. Comparison with the inactive conformation reveals that cAMP binding causes conformational changes that allow the cyclic nucleotide binding domain to swing from a position blocking the Rap binding site towards a docking site at the Ras exchange motif domain.

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