Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT1 receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ). © 2012 Miura et al.
CITATION STYLE
Miura, S. ichiro, Kiya, Y., Hanzawa, H., Nakao, N., Fujino, M., Imaizumi, S., … Saku, K. (2012). Small molecules with similar structures exhibit Agonist, neutral Antagonist or inverse Agonist activity toward Angiotensin II type 1 receptor. PLoS ONE, 7(6). https://doi.org/10.1371/journal.pone.0037974
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