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.
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.
Lescot
Elodie
E
Centre d'Etudes et de Recherche sur le Médicament de Normandie, Université de Caen, U.F.R. des Sciences Pharmaceutiques, 5 rue Vaubénard, 14032 Caen Cedex, France.
Sopkova-de Oliveira Santos
Jana
J
Colloc'h
Nathalie
N
Rodrigo
Jordi
J
Milazzo-Segalas
Isabelle
I
Bureau
Ronan
R
Rault
Sylvain
S
D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000737:chemistry; D000818:Animals; D001552:Benzazepines / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D014579:Urotensins / Q000737:chemistry* / Q000378:metabolism
D000634:Aminoquinolines; D001552:Benzazepines; D008024:Ligands; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; D014508:Urea; D012243:Rhodopsin; C029677:urotensin II