Mizwicki Mathew T, Keidel Don, Bula Craig M, Bishop June E, Zanello Laura P, Wurtz Jean-Marie, Moras Dino, Norman Anthony W
Department of Biochemistry, University of California, Riverside, CA 92521, USA.
Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12876-81. doi: 10.1073/pnas.0403606101. Epub 2004 Aug 23.
Structural and molecular studies have shown that the vitamin D receptor (VDR) mediates 1alpha,25(OH)2-vitamin D3 gene transactivation. Recent evidence indicates that both VDR and the estrogen receptor are localized to plasma membrane caveolae and are required for initiation of nongenomic (NG) responses. Computer docking of the NG-specific 1alpha,25(OH)2-lumisterol to the VDR resulted in identification of an alternative ligand-binding pocket that partially overlaps the genomic pocket described in the experimentally determined x-ray structure. Data obtained from docking five different vitamin D sterols in the genomic and alternative pockets were used to generate a receptor conformational ensemble model, providing an explanation for how VDR and possibly the estrogen receptor can have genomic and NG functionality. The VDR model is compatible with the following: (i) NG chloride channel agonism and antagonism; (ii) variable ligand-stabilized trypsin digest banding patterns; and (iii) differential transcriptional activity, employing different VDR point mutants and 1alpha,25(OH)2-vitamin D3 analogs.
结构和分子研究表明，维生素D受体（VDR）介导1α,25(OH)2 - 维生素D3基因的反式激活。最近的证据表明，VDR和雌激素受体都定位于质膜小窝，并且是非基因组（NG）反应启动所必需的。将NG特异性的1α,25(OH)2 - 光甾醇与VDR进行计算机对接，结果鉴定出一个与实验测定的X射线结构中描述的基因组口袋部分重叠的替代配体结合口袋。从在基因组口袋和替代口袋中对接五种不同的维生素D甾醇获得的数据用于生成受体构象集合模型，从而解释了VDR以及可能的雌激素受体如何具有基因组和NG功能。VDR模型与以下情况相符：（i）NG氯离子通道激动作用和拮抗作用；（ii）可变的配体稳定的胰蛋白酶消化条带模式；以及（iii）采用不同的VDR点突变体和1α,25(OH)2 - 维生素D3类似物的差异转录活性。
