Probing a water channel near the A-ring of receptor-bound 1α,25-dihydroxyvitamin D3 with selected 2α-substituted analogues
Probing a water channel near the A-ring of receptor-bound 1α,25-dihydroxyvitamin D3 with selected 2α-substituted analogues
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DOI：
10.1021/jm0604070
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发表时间：
2006-08-24
影响因子：
7.3
通讯作者：
Moras, Dino
中科院分区：
文献类型：
--
作者：
Hourai, Shinji;Fujishima, Toshie;Moras, Dino
维生素D受体（VDR）与1 α，25（OH）（2）D-3复合物的晶体结构显示，在A环附近存在几个水分子，将配体C-2位置连接到蛋白质表面。在这里，我们报告的晶体结构的人VDR配体结合域结合到选定的C-2 α取代的类似物，即，甲基，丙基，丙氧基，羟丙基，和羟丙氧基。这些特定的取代不会改变蛋白质或配体的结构，但除了甲基取代基之外，所有类似物都会影响上述水分子的存在和/或位置。通道相互作用的完整性和特异性C-2 α类似物导向的额外相互作用与配体的结合亲和力相关。相反，所产生的H-键的损失或获得并不反映HL 60细胞分化的幅度。我们的总体研究结果突出了一个合理的方法来设计更有效的配体，通过建立在晶体结构中揭示的功能。
The crystal structure of the vitamin D receptor (VDR) in complex with 1 alpha, 25(OH)(2)D-3 revealed the presence of several water molecules near the A-ring linking the ligand C-2 position to the protein surface. Here, we report the crystal structures of the human VDR ligand binding domain bound to selected C-2 alpha substituted analogues, namely, methyl, propyl, propoxy, hydroxypropyl, and hydroxypropoxy. These specific replacements do not modify the structure of the protein or the ligand, but with the exception of the methyl substituent, all analogues affect the presence and/or the location of the above water molecules. The integrity of the channel interactions and specific C-2 alpha analogue directed additional interactions correlate with the binding affinity of the ligands. In contrast, the resulting loss or gain of H-bonds does not reflect the magnitude of HL60 cell differentiation. Our overall findings highlight a rational approach to the design of more potent ligands by building in features revealed in the crystal structures.