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Small molecules with similar structures exhibit agonist, neutral antagonist or inverse agonist activity toward angiotensin II type 1 receptor.

Miura S, Kiya Y, Hanzawa H, Nakao N, Fujino M, Imaizumi S, Matsuo Y, Yanagisawa H, Koike H, Komuro I, Karnik SS, Saku K - PLoS ONE (2012)

Bottom Line: 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(1) 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. miuras@cis.fukuoka-u.ac.jp

ABSTRACT
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(1) 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).

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A. Summary of cysteine accessibilityat Ser109, Leu112, Val116 and Phe117 with olmesartan, R239470 and R794847 compared to ligand (-).Less and More indicate that the AT1 receptor is less or more accessible to the ligand pocket, respectively. B. Helical wheel representation of transmenbrane (TM)3 cysteine residues for ligand (-), olmesartan, R239470 and R794847. Olmesartan induced the outward displacement and counterclockwise rotation of TM3. Dotted circle indicates the original position of TM3 without ligand. Accessible area indicates a site of ligand pocket. C. Schematic view of TM3 movement derived from the SCAM results. TM3 without ligand is shown as a gray ribbon and TM3 with various ligands is represented as green ribbons. The ligands are colored magenta. (a) without ligand, (b) olmesartan, (c) R239470, (d) R794847.
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pone-0037974-g004: A. Summary of cysteine accessibilityat Ser109, Leu112, Val116 and Phe117 with olmesartan, R239470 and R794847 compared to ligand (-).Less and More indicate that the AT1 receptor is less or more accessible to the ligand pocket, respectively. B. Helical wheel representation of transmenbrane (TM)3 cysteine residues for ligand (-), olmesartan, R239470 and R794847. Olmesartan induced the outward displacement and counterclockwise rotation of TM3. Dotted circle indicates the original position of TM3 without ligand. Accessible area indicates a site of ligand pocket. C. Schematic view of TM3 movement derived from the SCAM results. TM3 without ligand is shown as a gray ribbon and TM3 with various ligands is represented as green ribbons. The ligands are colored magenta. (a) without ligand, (b) olmesartan, (c) R239470, (d) R794847.

Mentions: We summarized whether Ser109, Leu112, Val116 and Phe117 become more or less accessible in the ligand pocket with olmesartan, R794847 or R239470 compared to ligand (-) (Fig. 4a). Since olmesartan showed less accessibility at Ser109 and Leu112, TM3 was shifted outward from the ligand pocket (Fig. 4bc). In addition, since olmesartan induced greater accessibility at Phe117, TM3 might show slight counterclockwise rotation. R239470 only induced a small conformational change in TM3. Since only Leu112 was less accessible with R239470, TM3 may be only slightly shifted outward from the ligand pocket. R794847 showed conformational changes similar to those with olmesartan. Since R794847 showed less accessibility at Ser109 and Leu112 and more accessibility at Val116 and Phe117, TM3 was shifted outward from the ligand pocket and showed greater counterclockwise rotation than with olmesartan.


Small molecules with similar structures exhibit agonist, neutral antagonist or inverse agonist activity toward angiotensin II type 1 receptor.

Miura S, Kiya Y, Hanzawa H, Nakao N, Fujino M, Imaizumi S, Matsuo Y, Yanagisawa H, Koike H, Komuro I, Karnik SS, Saku K - PLoS ONE (2012)

A. Summary of cysteine accessibilityat Ser109, Leu112, Val116 and Phe117 with olmesartan, R239470 and R794847 compared to ligand (-).Less and More indicate that the AT1 receptor is less or more accessible to the ligand pocket, respectively. B. Helical wheel representation of transmenbrane (TM)3 cysteine residues for ligand (-), olmesartan, R239470 and R794847. Olmesartan induced the outward displacement and counterclockwise rotation of TM3. Dotted circle indicates the original position of TM3 without ligand. Accessible area indicates a site of ligand pocket. C. Schematic view of TM3 movement derived from the SCAM results. TM3 without ligand is shown as a gray ribbon and TM3 with various ligands is represented as green ribbons. The ligands are colored magenta. (a) without ligand, (b) olmesartan, (c) R239470, (d) R794847.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375280&req=5

pone-0037974-g004: A. Summary of cysteine accessibilityat Ser109, Leu112, Val116 and Phe117 with olmesartan, R239470 and R794847 compared to ligand (-).Less and More indicate that the AT1 receptor is less or more accessible to the ligand pocket, respectively. B. Helical wheel representation of transmenbrane (TM)3 cysteine residues for ligand (-), olmesartan, R239470 and R794847. Olmesartan induced the outward displacement and counterclockwise rotation of TM3. Dotted circle indicates the original position of TM3 without ligand. Accessible area indicates a site of ligand pocket. C. Schematic view of TM3 movement derived from the SCAM results. TM3 without ligand is shown as a gray ribbon and TM3 with various ligands is represented as green ribbons. The ligands are colored magenta. (a) without ligand, (b) olmesartan, (c) R239470, (d) R794847.
Mentions: We summarized whether Ser109, Leu112, Val116 and Phe117 become more or less accessible in the ligand pocket with olmesartan, R794847 or R239470 compared to ligand (-) (Fig. 4a). Since olmesartan showed less accessibility at Ser109 and Leu112, TM3 was shifted outward from the ligand pocket (Fig. 4bc). In addition, since olmesartan induced greater accessibility at Phe117, TM3 might show slight counterclockwise rotation. R239470 only induced a small conformational change in TM3. Since only Leu112 was less accessible with R239470, TM3 may be only slightly shifted outward from the ligand pocket. R794847 showed conformational changes similar to those with olmesartan. Since R794847 showed less accessibility at Ser109 and Leu112 and more accessibility at Val116 and Phe117, TM3 was shifted outward from the ligand pocket and showed greater counterclockwise rotation than with olmesartan.

Bottom Line: 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(1) 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).

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan. miuras@cis.fukuoka-u.ac.jp

ABSTRACT
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(1) 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).

Show MeSH