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 A 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.
Lavecchia
Antonio
A
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy. lavecchi@unina.it
Cosconati
Sandro
S
Novellino
Ettore
E
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment
D008024:Ligands; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D012243:Rhodopsin