Vitamin D Analogues with a p-Hydroxyphenyl Group at the C25 Position: Crystal Structure of Vitamin D Receptor Ligand-Binding Domain Complexed with the Ligand Explains the Mechanism Underlying Full Antagonistic Action
Vitamin D Analogues with a p-Hydroxyphenyl Group at the C25 Position: Crystal Structure of Vitamin D Receptor Ligand-Binding Domain Complexed with the Ligand Explains the Mechanism Underlying Full Antagonistic Action
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DOI：
10.1021/acs.jmedchem.7b00819
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发表时间：
2017-10-26
影响因子：
7.3
通讯作者：
Yamamoto, Keiko
中科院分区：
文献类型：
--
作者：
Kato, Akira;Yamao, Makiko;Yamamoto, Keiko
维生素D受体(VDR)拮抗剂可分为两类：第一类VDR拮抗剂不稳定螺旋11？12区，第二类拮抗剂破坏螺旋6？7区的稳定。为了利用晶体结构阐明第一类拮抗剂的作用机理，我们设计并合成了几个C25-位带有对羟基苯基的VDR配体。其中，22S-丁基-25-羰基类似物5b和25-二对羟氧基苯基类似物6a、b表现出较强的拮抗活性。我们成功地将VDR与5b络合物的配体结合域共结晶，发现其结构显示了螺旋11？12的替代构象，这解释了第一类拮抗剂的作用机制。综合目前和以往的研究，我们可以根据个体的晶体结构来阐明第一类和第二类拮抗剂的作用机制。这项研究不仅对VDR而且对核受体的拮抗作用提供了重要的见解。
Vitamin D receptor (VDR) antagonists can be classified into two categories: the first category of VDR antagonists, which do not stabilize the helix 11?12, and the second category of antagonists, which destabilize the helix 6?7 region. To elucidate the mechanism underlying the first category antagonists by using the crystal structure, we designed and synthesized several VDR ligands with a p-hydroxyphenyl group at the C25-position. Of these, 22S-butyl-25-carbonyl analogue 5b and 25-di-p-hydoroxyphenyl analogues 6a,b showed strong antagonistic activity. We succeeded in cocrystallizing the ligand-binding domain of VDR complexed with 5b and found that the structure showed an alternative conformation of the helix 11?12 that explained the mechanism of the first category antagonists. Taking the present and previous studies together, we could elucidate the mechanisms underlying first and second categories antagonists based on individual crystal structures. This study provides significant insights into antagonism against not only VDR but also nuclear receptors.