Architecture of the human urotensin II receptor: Comparison of the binding domains of peptide and non-peptide urotensin II agonists

The human urotensin II receptor (h-UTR) is a member of the family of rhodopsin-like G-protein-coupled receptors (GPCRs) involved in the modulation of the functionality of many tissues and organs. Recently the urotensin-II (UII) neuropeptide, which is a potent vasoconstrictor in mammals and it is postulated to play a central role in cardiovascular homeostasis, has been identified as an agonist of the UII receptor. To elucidate the receptor's molecular recognition, a h-UTR model was constructed by homology modeling using the 2.6 Å crystal structure of bovine rhodopsin as a template and subsequently refined by molecular dynamics simulations. The molecular recognition of h-UTR was probed by automated docking of P5U, a potent UII peptide agonist, as well as of the non-peptide compounds 1-4. We believe that this new model of the h-UTR provides the means for understanding the ligand's potency and for facilitating the design of novel and more potent UII ligands. © 2005 American Chemical Society.