Paper Citing NAMD - Abstract
Kim, Soo-Kyung; Li, Youyong; Park, Changmoon; Abrol, Ravinder; Goddard, William A., I.I.I.
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, SEP 3 2010
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 similar to 4 nm in a molecular binding assay, but it is reported to bind weakly to rat UT2R (rUT2R), with a K(d) value of similar to 1 500 nm. In contrast, the arylsulphonamide SB706375 is a selective antagonist against both hUT2R (K(d) = similar to 9 nm) and rUT2R (K(d) = similar to 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 (similar to 400-fold) affinity of ACT058362 for rUT2R and the similar affinity (similar to 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- arylor 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.
