Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor
5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling
Gespeichert in:
| Autor*in: |
Habib Abul Muntasir [verfasserIn] Mamunur Rashid [verfasserIn] Tadazumi Komiyama [verfasserIn] Jun Kawakami [verfasserIn] Takafumi Nagatomo [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2006 |
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| Übergeordnetes Werk: |
In: Journal of Pharmacological Sciences - Elsevier, 2017, 102(2006), 1, Seite 55-63 |
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| Übergeordnetes Werk: |
volume:102 ; year:2006 ; number:1 ; pages:55-63 |
| Links: |
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| DOI / URN: |
10.1254/jphs.FP0060171 |
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DOAJ035442972 |
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| 520 | |a The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling | ||
| 653 | 0 | |a Therapeutics. Pharmacology | |
| 700 | 0 | |a Mamunur Rashid |e verfasserin |4 aut | |
| 700 | 0 | |a Tadazumi Komiyama |e verfasserin |4 aut | |
| 700 | 0 | |a Jun Kawakami |e verfasserin |4 aut | |
| 700 | 0 | |a Takafumi Nagatomo |e verfasserin |4 aut | |
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10.1254/jphs.FP0060171 doi (DE-627)DOAJ035442972 (DE-599)DOAJce111e66bd294ef69ae4f21f741d38ca DE-627 ger DE-627 rakwb eng RM1-950 Habib Abul Muntasir verfasserin aut Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling Therapeutics. Pharmacology Mamunur Rashid verfasserin aut Tadazumi Komiyama verfasserin aut Jun Kawakami verfasserin aut Takafumi Nagatomo verfasserin aut In Journal of Pharmacological Sciences Elsevier, 2017 102(2006), 1, Seite 55-63 (DE-627)1760631620 13478613 nnns volume:102 year:2006 number:1 pages:55-63 https://doi.org/10.1254/jphs.FP0060171 kostenfrei https://doaj.org/article/ce111e66bd294ef69ae4f21f741d38ca kostenfrei http://www.sciencedirect.com/science/article/pii/S1347861319344160 kostenfrei https://doaj.org/toc/1347-8613 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 102 2006 1 55-63 |
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10.1254/jphs.FP0060171 doi (DE-627)DOAJ035442972 (DE-599)DOAJce111e66bd294ef69ae4f21f741d38ca DE-627 ger DE-627 rakwb eng RM1-950 Habib Abul Muntasir verfasserin aut Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling Therapeutics. Pharmacology Mamunur Rashid verfasserin aut Tadazumi Komiyama verfasserin aut Jun Kawakami verfasserin aut Takafumi Nagatomo verfasserin aut In Journal of Pharmacological Sciences Elsevier, 2017 102(2006), 1, Seite 55-63 (DE-627)1760631620 13478613 nnns volume:102 year:2006 number:1 pages:55-63 https://doi.org/10.1254/jphs.FP0060171 kostenfrei https://doaj.org/article/ce111e66bd294ef69ae4f21f741d38ca kostenfrei http://www.sciencedirect.com/science/article/pii/S1347861319344160 kostenfrei https://doaj.org/toc/1347-8613 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 102 2006 1 55-63 |
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10.1254/jphs.FP0060171 doi (DE-627)DOAJ035442972 (DE-599)DOAJce111e66bd294ef69ae4f21f741d38ca DE-627 ger DE-627 rakwb eng RM1-950 Habib Abul Muntasir verfasserin aut Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling Therapeutics. Pharmacology Mamunur Rashid verfasserin aut Tadazumi Komiyama verfasserin aut Jun Kawakami verfasserin aut Takafumi Nagatomo verfasserin aut In Journal of Pharmacological Sciences Elsevier, 2017 102(2006), 1, Seite 55-63 (DE-627)1760631620 13478613 nnns volume:102 year:2006 number:1 pages:55-63 https://doi.org/10.1254/jphs.FP0060171 kostenfrei https://doaj.org/article/ce111e66bd294ef69ae4f21f741d38ca kostenfrei http://www.sciencedirect.com/science/article/pii/S1347861319344160 kostenfrei https://doaj.org/toc/1347-8613 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 102 2006 1 55-63 |
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10.1254/jphs.FP0060171 doi (DE-627)DOAJ035442972 (DE-599)DOAJce111e66bd294ef69ae4f21f741d38ca DE-627 ger DE-627 rakwb eng RM1-950 Habib Abul Muntasir verfasserin aut Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling Therapeutics. Pharmacology Mamunur Rashid verfasserin aut Tadazumi Komiyama verfasserin aut Jun Kawakami verfasserin aut Takafumi Nagatomo verfasserin aut In Journal of Pharmacological Sciences Elsevier, 2017 102(2006), 1, Seite 55-63 (DE-627)1760631620 13478613 nnns volume:102 year:2006 number:1 pages:55-63 https://doi.org/10.1254/jphs.FP0060171 kostenfrei https://doaj.org/article/ce111e66bd294ef69ae4f21f741d38ca kostenfrei http://www.sciencedirect.com/science/article/pii/S1347861319344160 kostenfrei https://doaj.org/toc/1347-8613 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 102 2006 1 55-63 |
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10.1254/jphs.FP0060171 doi (DE-627)DOAJ035442972 (DE-599)DOAJce111e66bd294ef69ae4f21f741d38ca DE-627 ger DE-627 rakwb eng RM1-950 Habib Abul Muntasir verfasserin aut Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor 2006 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling Therapeutics. Pharmacology Mamunur Rashid verfasserin aut Tadazumi Komiyama verfasserin aut Jun Kawakami verfasserin aut Takafumi Nagatomo verfasserin aut In Journal of Pharmacological Sciences Elsevier, 2017 102(2006), 1, Seite 55-63 (DE-627)1760631620 13478613 nnns volume:102 year:2006 number:1 pages:55-63 https://doi.org/10.1254/jphs.FP0060171 kostenfrei https://doaj.org/article/ce111e66bd294ef69ae4f21f741d38ca kostenfrei http://www.sciencedirect.com/science/article/pii/S1347861319344160 kostenfrei https://doaj.org/toc/1347-8613 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA AR 102 2006 1 55-63 |
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Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). 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Habib Abul Muntasir |
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RM1-950 Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor |
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Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor |
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identification of amino acid residues important for sarpogrelate binding to the human 5-hydroxytryptamine2a serotonin receptor |
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Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor |
| abstract |
The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling |
| abstractGer |
The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling |
| abstract_unstemmed |
The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd <10,000 nM). Therefore, it was not possible to find any sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies. Keywords:: 5-hydroxytryptamine (5-HT), 5-HT2A receptor, sarpogrelate, site-directed mutagenesis, molecular modeling |
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