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首页> 外文期刊>Journal of Medicinal Chemistry >Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: Structural basis for vitamin D receptor antagonism and partial agonism
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Crystal structures of rat vitamin D receptor bound to adamantyl vitamin D analogs: Structural basis for vitamin D receptor antagonism and partial agonism

机译：与金刚烷基维生素D类似物结合的大鼠维生素D受体的晶体结构：维生素D受体拮抗和部分激动的结构基础

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摘要

The X-ray crystal structures of the rat VDR ligand-binding domain complexed with 19-norvitamin D compound,, that contain an adamantyl substituent at the side-chain terminus, 2a (ADTT), 2b (ADNY), and 2c (ADMI4) and a coactivator peptide derived from DRIP205 are reported. These compounds show a series of partial agonistic (10-75% efficacy)/antagonistic activities. All of these complexed receptors are crystallized in the canonical active conformation, regardless of their activity profiles. The bulky adamantyl side chain does not crowd helix 12 but protrudes into the gap formed by helix 11, loop 11-12, helix 3, and loop 6-7, thereby widening the ligand binding pocket. We suggest that these structural changes destabilize the active protein conformation and reduce its contribution to equilibrium among the active and inactive conformations. The coactivator peptide traps the minor active conformation, and the equilibrium shifts to the active conformation. As a result, these ligands show partial agonistic activities.
机译：与19-去甲维生素D化合物复合的大鼠VDR配体结合域的X射线晶体结构，在侧链末端含金刚烷基取代基，2a（ADTT），2b（ADNY）和2c（ADMI4）报道了源自DRIP205的共激活肽。这些化合物表现出一系列的部分激动作用（10-75％功效）/拮抗活性。所有这些复合受体均以规范的活性构象结晶，无论其活性谱如何。庞大的金刚烷基侧链不拥挤螺旋12，而是突入由螺旋11，环11-12，螺旋3和环6-7形成的间隙中，从而加宽了配体结合口袋。我们建议，这些结构变化会破坏活性蛋白构象的稳定性，并减少其对活性构象和非活性构象之间平衡的贡献。辅助活化剂肽捕获次要的活性构象，并且平衡转变为活性构象。结果，这些配体显示出部分激动活性。

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