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Identification of the Histidine Residue in Vitamin D Receptor That Covalently Binds to Electrophilic Ligands
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-23 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00774 Mami Yoshizawa 1 , Toshimasa Itoh 1 , Tatsuya Hori 1 , Akira Kato 1 , Yasuaki Anami 1 , Nobuko Yoshimoto 1 , Keiko Yamamoto 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-06-23 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00774 Mami Yoshizawa 1 , Toshimasa Itoh 1 , Tatsuya Hori 1 , Akira Kato 1 , Yasuaki Anami 1 , Nobuko Yoshimoto 1 , Keiko Yamamoto 1
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We designed and synthesized vitamin D analogues with an electrophile as covalent modifiers for the vitamin D receptor (VDR). Novel vitamin D analogues 1–4 have an electrophilic enone group at the side chain for conjugate addition to His301 or His393 in the VDR. All compounds showed specific VDR-binding potency and agonistic activity. Covalent bond formations of 1–4 with the ligand-binding domain (LBD) of VDR were evaluated by electrospray ionization mass spectrometry. All compounds were shown to covalently bind to the VDR-LBD, and the abundance of VDR-LBD corresponding conjugate adducts of 1–4 increased with incubation time. Enone compounds 1 and 2 showed higher reactivity than the ene-ynone 3 and dienone 4 compounds. Furthermore, we successfully obtained cocrystals of VDR-LBD with analogues 1–4. X-ray crystallographic analysis showed a covalent bond with His301 in VDR-LBD. We successfully synthesized vitamin D analogues that form a covalent bond with VDR-LBD.
中文翻译：
共价结合亲电配体的维生素D受体中组氨酸残基的鉴定
我们设计并合成了具有亲电子试剂的维生素D类似物，作为维生素D受体（VDR）的共价修饰剂。新的维生素d类似物1 - 4具有在侧链共轭除了His301或His393在VDR亲电烯酮基团。所有化合物均显示出特定的VDR结合效能和激动活性。的共价键的形成1 - 4与VDR的配体结合域（LBD），通过电喷雾电离质谱评价。所有化合物均显示出共价结合到VDR-LBD，和相应的共轭加成物VDR-LBD的丰度1 - 4与温育时间而增加。烯酮化合物1和图2显示出比烯-炔酮3和二烯酮4化合物更高的反应性。此外，我们成功地获得VDR-LBD的共晶体与类似物1 - 4。X射线晶体学分析显示在VDR-LBD中与His301共价键。我们成功地合成了与VDR-LBD形成共价键的维生素D类似物。
更新日期：2018-06-23
中文翻译：
共价结合亲电配体的维生素D受体中组氨酸残基的鉴定
我们设计并合成了具有亲电子试剂的维生素D类似物，作为维生素D受体（VDR）的共价修饰剂。新的维生素d类似物1 - 4具有在侧链共轭除了His301或His393在VDR亲电烯酮基团。所有化合物均显示出特定的VDR结合效能和激动活性。的共价键的形成1 - 4与VDR的配体结合域（LBD），通过电喷雾电离质谱评价。所有化合物均显示出共价结合到VDR-LBD，和相应的共轭加成物VDR-LBD的丰度1 - 4与温育时间而增加。烯酮化合物1和图2显示出比烯-炔酮3和二烯酮4化合物更高的反应性。此外，我们成功地获得VDR-LBD的共晶体与类似物1 - 4。X射线晶体学分析显示在VDR-LBD中与His301共价键。我们成功地合成了与VDR-LBD形成共价键的维生素D类似物。
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