Morizono Daisuke
Graduate School of Medical and Dental Sciences, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University.
J Med Dent Sci. 2011 Dec 28;58(4):103-12.
Nuclear receptors mediate allosteric communications where ligand binding initiates a cascade of signal transduction. The interaction of vitamin D with vitamin D receptor (VDR) was investigated by (19)F NMR spectroscopy of the complexes of three fluorinated vitamin D derivatives with the full-length rat VDR-LBD. In the (19)F NMR spectra of the VDR-ligand complexes, the A-ring of 4,4-difluoro-1,25(OH)2D3 was revealed to adopt β-conformation in the VDR in solution, and the spectra were shown to be dependent on the dissociation constant. While the complex of 4,4-difluoro-1,25(OH)2D3 with VDR exhibited a clear distinguishable (19)F NMR spectrum, those of (19)F-1,25(OH)2D3 stereoisomers, which have 10-fold higher VDR affinity than 4,4-difluoro-1,25(OH)2D3, did not. The solid-phase NMR technique was useful for (19)F-1,25(OH)2D3 stereoisomers. The fluorinated vitamin D derivatives showed marked changes in the chemical shift (Δ4-19.7 ppm) upon VDR-complex formation, and the ab initio MO method suggested that van der Waals interactions play a major role in the complex formation.
核受体介导变构通讯，其中配体结合引发信号转导级联反应。通过对三种氟化维生素D衍生物与全长大鼠维生素D受体配体结合域（VDR-LBD）复合物的（19）F核磁共振光谱研究了维生素D与维生素D受体（VDR）的相互作用。在VDR-配体复合物的（19）F核磁共振光谱中，4,4-二氟-1,25（OH）2D3的A环在溶液中的VDR中呈现β构象，并且光谱显示取决于解离常数。虽然4,4-二氟-1,25（OH）2D3与VDR的复合物表现出清晰可辨的（19）F核磁共振光谱，但（19）F-1,25（OH）2D3立体异构体的光谱却没有，其对VDR的亲和力比4,4-二氟-1,25（OH）2D3高10倍。固相核磁共振技术对（19）F-1,25（OH）2D3立体异构体很有用。氟化维生素D衍生物在形成VDR复合物后化学位移发生显著变化（Δ4 - 19.7 ppm），并且从头算分子轨道方法表明范德华相互作用在复合物形成中起主要作用。
