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甲状腺ホルモンとリガンドの結合におけるハロゲン原子の受容体結合力増強機構の解明

阐明卤素原子增强甲状腺激素与配体结合中受体结合力的机制

基本信息

批准号：
18J11638
负责人：
袈裟丸仁志
金额：
$ 0.96万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2018
资助国家：
日本
起止时间：
2018-04-25 至 2020-03-31
项目状态：
已结题

项目摘要

甲状腺ホルモン受容体(TRs)は、全身の細胞に発現し、トリヨードチロニン(T3)やチロキシン(T4)が結合することで活性化し、細胞の代謝を向上させる。TRの内在性リガンドであるT4は、分子中に4つのヨウ素原子を持つが、チロキシン類縁体のホルモン活性はヨウ素の位置や数に依存すること、ヨウ素を持たないチロニンはTRに対して活性を示さないことが報告されている。本研究の目的は、TRとT4をはじめとするTR結合性リガンドとの間の結合におけるハロゲン原子の寄与を解明し、チロニン誘導体の受容体結合機構の解明と定量的な化学物質の核内受容体結合性予測法の確立を目指すことである。本年度は、取り扱いに専用の施設が必要となる放射標識化合物を用いた試験に替わる蛍光標識化合物による試験系の確立と、それを用いたTR結合性リガンドの結合性評価を試みた。その結果、初めに、定量的な化学物質の受容体結合性を評価するのに用いる蛍光リガンドT4-C6-NBDの合成し、合成したリガンドを用いての結合試験系の確立、さらにハロゲン含有化合物の結合性評価を達成した。このことは、取扱に制限のある放射標識リガンドを用いることなく、一般の実験室においても簡便かつ高感度な結合競争試験を実施可能とするため、今後のTRsに関する研究を飛躍的に進展させることが期待される。さらに、確立した結合試験系を用いることで、臭素4置換BPA（TBBPA）やヨウ素4置換BPA（TIBPA）がTRに非常に強く結合することを明らかとした。このことは、TRsへのリガンドの結合には芳香環オルト位に対し臭素原子やヨウ素原子といった大きな置換基が必要であることを明らかとし、また、ヨウ素原子以外の置換によって結合性がさらに増強されるという化学物質リスクに関する有益な知見が得られたと考えられた。

Thyroid gland receptor (TRs), whole body tumor cells were detected, thyroid gland cells (T3) and thyroid cells (T4) were combined with the activation of thyroid cells, and the cells were replaced by upward cells. TR has an intrinsic effect on T4, an atom in a molecule that holds an atom, an atom that is active in a molecule, and a cell in which the position of an element is dependent on the number of positions in which it is active. The number of positions in which the position of the element is dependent, the activity of the molecule, the activity of the TR, the activity of the molecule, the position of the element, the number of In this study, the purpose of this study was to determine the binding capacity of the chemical compounds in the nucleus of the chemical compounds by means of the combination of chemical compounds in the nuclei of the chemical compounds. The purpose of this study was to determine the binding capacity of the chemical compounds in the nucleus of the chemical compounds by means of the combination of the atoms and the capacitive bodies in the TR. This year, it is necessary to use the equipment to replace the radiation identification compounds. this year, we use the equipment to determine the accuracy of the optical identification compounds. this year, we use the necessary equipment to replace the radiation identification compounds. this year, we use the equipment to determine the accuracy of the radiation labeling compounds. this year, we use the equipment to determine the accuracy of the radiation identification compounds. this year, we use the equipment to determine the accuracy of the radiation labeling compounds. this year, we use the equipment to determine the accuracy of the radiation labeling compounds. this year, we use the equipment to determine the accuracy of the radiation labeling compounds. this year, we use the equipment to determine the accuracy of the optical identification compounds. this year, we use the equipment to determine the accuracy of the optical identification compounds. this year, we use the equipment to determine the accuracy of the optical identification compounds. The results, the preliminary results, the quantitative analysis of the chemical compounds, the binding properties of the capacitors, the synthesis of the compounds, the combination of the compounds, the synthesis of the compounds, the results of the results, the results of the results, the preliminary results, the quantitative analysis of the chemical compounds, the combination of the compounds, the synthesis of the compounds, the combination of the compounds, the synthesis of the compounds, the combination of the compounds, the combination of the compounds, the synthesis of the compounds, the results of the results, the results of the results, the preliminary results, the quantitative chemical compounds, the binding properties of the compounds, the synthesis of the compounds, the combination of the compounds In the future, the development of TRs research in recent years is expected to improve the performance of the radiation industry. It is necessary to use the combination of BPA (TBBPA), BPA (TIBPA) and TR to make sure that the combination is very important. The combination of the aromatic compounds, the TRs atoms, the aromatic compounds, the aromatic compounds, the aromatic atoms, the aromatic atoms, the aromatic atoms