論文 - 詳細
| RRC ID | 54785 |
|---|---|
| 著者 | Hishinuma S, Tamura Y, Kobayashi C, Akatsu C, Shoji M. |
| タイトル | Differential Regulation of Thermodynamic Binding Forces of Levocetirizine and (S)-Cetirizine by Lys191 in Human Histamine H₁ Receptors. |
| ジャーナル | Int J Mol Sci |
| Abstract |
Cetirizine is a zwitterionic second-generation antihistamine containing R- and S-enantiomers, levocetirizine, and (S)-cetirizine. Levocetirizine is known to have a higher affinity for the histamine H₁ receptors than (S)-cetirizine; ligand-receptor docking simulations have suggested the importance of the formation of a salt bridge (electrostatic interaction) between the carboxylic group of levocetirizine and the Lys191 residue at the fifth transmembrane domain of human histamine H₁ receptors. In this study, we evaluated the roles of Lys191 in the regulation of the thermodynamic binding forces of levocetirizine in comparison with (S)-cetirizine. The binding enthalpy and entropy of these compounds were estimated from the van 't Hoff equation, by using the dissociation constants obtained from their displacement curves against the binding of [³H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing wild-type human H₁ receptors and their Lys191 mutants to alanine at various temperatures. We found that the higher binding affinity of wild-type H₁ receptors for levocetirizine than (S)-cetirizine was achieved by stronger forces of entropy-dependent hydrophobic binding of levocetirizine. The mutation of Lys191 to alanine reduced the affinities for levocetirizine and (S)-cetirizine, through a reduction in the entropy-dependent hydrophobic binding forces of levocetirizine and the enthalpy-dependent electrostatic binding forces of (S)-cetirizine. These results suggested that Lys191 differentially regulates the binding enthalpy and entropy of these enantiomers, and that Lys191 negatively regulates the enthalpy-dependent electrostatic binding forces of levocetirizine, contrary to the predictions derived from the ligand-receptor docking simulations. |
| 巻・号 | 19(12) |
| 公開日 | 2018-12-15 |
| DOI | 10.3390/ijms19124067 |
| PII | ijms19124067 |
| PMID | 30558340 |
| PMC | PMC6321019 |
| MeSH | Animals CHO Cells Cetirizine / pharmacology* Cricetulus Entropy Histamine H1 Antagonists, Non-Sedating / pharmacology* Humans Lysine / metabolism Protein Binding Receptors, Histamine H1 / metabolism* Thermodynamics |
| IF | 4.183 |
| 引用数 | 0 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | CHO-K1(RCB0285) |