Kim, Soo-Kyung and Li, Youyong and Park, Changmoon and Abrol, Ravinder and Goddard, William A. III (2010) Prediction of the Three-Dimensional Structure for the Rat Urotensin II Receptor, and Comparison of the Antagonist Binding Sites and Binding Selectivity between Human and Rat Receptors from Atomistic Simulations. Chemmedchem, 5 (9). pp. 1594-1608. ISSN 1860-7179 http://resolver.caltech.edu/CaltechAUTHORS:20101026-081332237
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Urotensin-II (U-II) has been shown to be the most potent mammalian vasoconstrictor known. Thus, a U-II antagonist might be of therapeutic value in a number of cardiovascular disorders. However, interspecies variability of several nonpeptidic ligands complicates the interpretation of in vivo studies of such antagonists in preclinical animal disease models. ACT058362 is a selective antagonist for the human U-II receptor (hUT2R) with a reported K_d value of ∼4 nM in a molecular binding assay, but it is reported to bind weakly to rat UT2R (rUT2R), with a K_d value of ∼1 500 nM. In contrast, the arylsulphonamide SB706375 is a selective antagonist against both hUT2R (K_d=∼9 nM) and rUT2R (K_d=∼21 nM). To understand the species selectivity of the UT2R, we investigated the binding site of ACT058362 and SB706375 in both hUT2R and rUT2R to explain the dramatically lower (∼400-fold) affinity of ACT058362 for rUT2R and the similar affinity (∼10 nM) of SB706375 for both UT2Rs. These studies used MembStruk and MSCDock to predict the UT2R structure and the binding site of ACT058362 and SB706375. Based on binding energies, we found two binding modes each with D130^(3.32) as the crucial anchoring point (Ballesteros–Weinstein numbering given in superscript). We predict that ACT058362 (an aryl–amine–aryl or ANA ligand) binds in the transmembrane (TM) 3456 region, while SB706375 (an aryl–aryl–amine or AAN ligand) binds in the TM 1237 region. These predicted sites explain the known differences in binding of the ANA ligand to rat and human receptors, while explaining the similar binding of the AAN compound to rat and human receptors. Moreover the predictions explain currently available structure–activity relationship (SAR) data. To further validate the predicted binding sites of these ligands in hUT2R and rUT2R, we propose several mutations that would help define the structural origins of differential responses between UT2R of different species, potentially indicating novel UT2R antagonists with cross-species high affinity.
|Additional Information:||© 2010 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim. Received: April 23, 2010. Revised: June 25, 2010. Published online on August 3, 2010. This work was funded partially by Boehringer-Ingelheim and by the National Institutes of Health (USA). In addition, the computational resources used here were provided by grants from ARODURIP and ONR-DURIP. We thank Ms. Lindsay Riley from the University of California (Los Angeles, USA) for helpful discussion.|
|Subject Keywords:||docking; G protein-coupled receptors; MembScream; MembStruk; molecular dynamics; urotensin II|
|Official Citation:||Kim, S.-K., Li, Y., Park, C., Abrol, R. and Goddard, W. (2010), Prediction of the Three-Dimensional Structure for the Rat Urotensin II Receptor, and Comparison of the Antagonist Binding Sites and Binding Selectivity between Human and Rat Receptors from Atomistic Simulations. ChemMedChem, 5: 1594–1608. doi: 10.1002/cmdc.201000175|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||24 Nov 2010 00:05|
|Last Modified:||26 Dec 2012 12:33|
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