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Three-dimensional model of the human urotensin-II receptor: docking of human urotensin-II and nonpeptide antagonists in the binding site and comparison with an antagonist pharmacophore model

Elodie Lescot, Jana Sopkova-de Oliveira Santos, Nathalie Colloc'h, Jordi Rodrigo, Isabelle Milazzo-Segalas, Ronan Bureau, Sylvain Rault
Proteins 2008, 73 (1): 173-84
18409194
Human urotensin-II (hU-II) is a cyclic peptide that plays a central role in cardiovascular homeostasis and is considered to be the most potent mammalian vasoconstrictor identified to date. It is a natural ligand of the human urotensin-II (hUT-II) receptor, a member of the family of rhodopsin-like G-protein-coupled receptors. To understand the molecular interactions of hU-II and certain antagonists with the hUT-II receptor, a model of the hUT-II receptor in an active conformation with all its connecting loops was constructed by homology modeling. The initial model was placed in a pre-equilibrated lipid bilayer and re-equilibrated by several procedures of energy minimization and molecular dynamics simulations. Docking studies were performed for hU-II and for a series of nonpeptide hUT-II receptor antagonists in the active site of the modeled receptor structure. Results of the hU-II docking study are in agreement with our previous work and with experimental data showing the contribution of the extracellular loops II and III to ligand recognition. The docking of hU-II nonpeptide antagonists allows identification of key molecular interactions and confirms a previously reported hU-II antagonist pharmacophore model. The results of the present studies will be used in structure-based drug design for developing novel antagonists for the hUT-II receptor.

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