Small Molecules with Similar Structures Exhibit Agonist, Neutral Antagonist or Inverse Agonist Activity toward Angiotensin II Type 1 Receptor Shin-ichiro Miura Yoshihiro Kiya Hiroyuki Hanzawa Naoki Nakao Masahiro Fujino Satoshi Imaizumi Yoshino Matsuo Hiroaki Yanagisawa Hiroyuki Koike Issei Komuro Sadashiva S. Karnik Keijiro Saku 10.1371/journal.pone.0037974 https://plos.figshare.com/articles/dataset/Small_Molecules_with_Similar_Structures_Exhibit_Agonist_Neutral_Antagonist_or_Inverse_Agonist_Activity_toward_Angiotensin_II_Type_1_Receptor/123990 <div><p>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 AT<sub>1</sub> 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).</p> </div> 2012-06-14 01:06:30 molecules structures antagonist inverse agonist angiotensin ii receptor