%0 Generic %A Miura, Shin-ichiro %A Kiya, Yoshihiro %A Hanzawa, Hiroyuki %A Nakao, Naoki %A Fujino, Masahiro %A Imaizumi, Satoshi %A Matsuo, Yoshino %A Yanagisawa, Hiroaki %A Koike, Hiroyuki %A Komuro, Issei %A Karnik, Sadashiva S. %A Saku, Keijiro %D 2012 %T Small Molecules with Similar Structures Exhibit Agonist, Neutral Antagonist or Inverse Agonist Activity toward Angiotensin II Type 1 Receptor %U 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 %R 10.1371/journal.pone.0037974 %2 https://plos.figshare.com/ndownloader/files/324258 %2 https://plos.figshare.com/ndownloader/files/324337 %2 https://plos.figshare.com/ndownloader/files/324401 %K molecules %K structures %K antagonist %K inverse %K agonist %K angiotensin %K ii %K receptor %X

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).

%I PLOS ONE