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The Vasoactive Intestinal Peptide (VIP) -Helix Up to C Terminus Interacts with the N-Terminal Ectodomain of the Human VIP/Pituitary Adenylate Cyclase-Activating Peptide 1 Receptor: Photoaffinity, Molecular Modeling, and Dynamics

Institut National de la Santé et de la Recherche Médicale Unité 773 (E.C., Y.-V.T., J.-J.L, A.C., M.L.), Centre de Recherche Biomédicale Bichat-Beaujon, CRB3, Faculté de Médecine Xavier Bichat, 75018 Paris, France; and Commissariat a l’Energie Atomique Division des Sciences du Vivant/Département de Biologie Joliot Curie (S.M., J.-M.N.), Unité de Recherche Associé Centre National de la Recherche Scientifique 2096, Centre d’Etudes de Saclay, 91191 Gif sur Yvette Cedex, France

Address all correspondence and requests for reprints to: Marc Laburthe, Institut National de la Santé et de la Recherche Médicale Unité 773, Faculté de Médecine Bichat, 16 rue Henri Huchard, 75018 Paris, France. E-mail: laburthe{at}bichat.inserm.fr.

The neuropeptide vasoactive intestinal peptide (VIP) strongly impacts on human pathophysiology and does so through interaction with class II G protein-coupled receptors. We characterized the C terminus-binding site of VIP in the N-terminal ectodomain (N-ted) of the human VPAC1 receptor: 1) The probe [¹²⁵I-Bpa²⁸]VIP in which the C-terminal residue (Asn²⁸) is substituted by a photoreactive p-benzoyl-L-Phe (Bpa) was used to photolabel the receptor. After receptor cleavage and Edman sequencing, it was shown that Asn²⁸ of VIP is in contact with Lys¹²⁷ in the receptor N-ted. Taking into account previous data, it follows that the C-terminal and central parts of VIP from Asn²⁸ to Phe⁶ lie in the N-ted. 2) A three-dimensional model of the N-ted was constructed, the fold being identified as a Sushi domain with two antiparallel β-sheets and three disulfide bonds. The nuclear magnetic resonance structure of VIP was then docked into this model by taking into account the constraint provided by photoaffinity experiments with [¹²⁵I-Bpa²⁸]VIP. It appeared that VIP runs parallel to the β3-β4 antiparallel sheets. 3) We performed molecular dynamic simulations over 14 nsec of the complex between VIP and receptor N-ted and the free N-ted. The structural model of the free N-ted is stable, and VIP tends to further stabilize the N-ted structure more especially in the loops connecting the β-sheets. These structural studies provide a detailed molecular understanding of the VIP-receptor interaction.

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