Peptide agonist docking in the N-terminal ectodomain of a class II G protein-coupled receptor, the VPAC1 receptor. Photoaffinity, NMR, and molecular modeling

The Journal of Biological Chemistry
Yossan-Var TanMarc Laburthe

Abstract

The neuropeptide vasoactive intestinal peptide (VIP) strongly impacts on human pathophysiology and does so through interaction with class II G protein-coupled receptors named VIP pituitary adenylate cyclase-activating peptide (PACAP) receptors (VPACs). The molecular nature of VIP binding to receptors remains elusive. In this work, we have docked VIP in the human VPAC1 receptor by the following approach. (i) VIP probes containing photolabile residues in positions 6, 22, and 24 of VIP were used to photolabel the receptor. After receptor cleavage and Edman sequencing of labeled receptor fragments, it was shown that Phe6, Tyr22, and Asn24 of VIP are in contact with Asp107, Gly116, and Cys122 in the N-terminal ectodomain (N-ted) of the receptor, respectively. (ii) The structure of VIP was determined by NMR showing a central alpha helix, a disordered N-terminal His1-Phe6 segment and a 3(10) Ser25-Asn28 helix termination. (iii) A three-dimensional model of the N-ted of hVPAC1 was constructed by using the NMR structure of the N-ted of corticotropin-releasing factor receptor 2beta as a template. As expected, the fold is identified as a short consensus repeat with two antiparallel beta sheets and is stabilized by three disulfide bonds. (...Continue Reading

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Citations

Jul 2, 2008·Journal of Molecular Neuroscience : MN·Alain CouvineauMarc Laburthe
Nov 14, 2013·Neuropeptides·Sanbing ShenDavid A Collier
Jun 24, 2011·Pancreas·Dorit FabriciusMary Sue O'Dorisio
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May 2, 2007·Proceedings of the National Academy of Sciences of the United States of America·Chaohong SunEdward T Olejniczak
Dec 27, 2008·Pharmacology & Therapeutics·Louise Dickson, Keith Finlayson
Jun 17, 2008·Trends in Biochemical Sciences·Jean-Michel NeumannMarc Laburthe
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