The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity
The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity
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DOI：
10.1126/science.1060762
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发表时间：
2001-06-22
期刊：
影响因子：
56.9
通讯作者：
Redinbo, MR
中科院分区：
文献类型：
--
作者：
Watkins, RE;Wisely, GB;Redinbo, MR
人类核妊娠X受体（hPXR）激活细胞色素P450-3A的表达以应对多种外源药物，并在介导危险的药物-药物相互作用中起关键作用。我们分别在2.5和2.75埃的分辨率下展示了hPXR单独和与降胆固醇药物SR12813复合的配体结合域的晶体结构。hPXR的疏水配体结合腔含有少量极性残基，允许SR12813在三个不同的方向上结合。发现这些极性残基的位置和性质对于建立PXR的精确药理激活谱至关重要。我们的发现为hPXR如何检测外源性药物提供了重要的见解，并可能在预测和避免药物相互作用方面证明是有用的。
The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.