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Nature 455, 124-127 (4 September 2008) | doi:10.1038/nature07187; Received 23 February 2008; Accepted 20 June 2008; Published online 27 July 2008

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Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B

Holger Rehmann1, Ernesto Arias-Palomo2, Michael A. Hadders3, Frank Schwede4, Oscar Llorca2 & Johannes L. Bos1

  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).

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Epac proteins are activated by binding of the second messenger cAMP and then act as guanine nucleotide exchange factors for Rap proteins1, 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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