Department of Chemistry, Biochemistry and Microbiology, University of North Carolina at Chapel Hill, 250 Bell Tower Drive, Chapel Hill, NC 27599, USA.
J Mol Biol. 2013 Jul 24;425(14):2561-77. doi: 10.1016/j.jmb.2013.04.012. Epub 2013 Apr 16.
The human nuclear xenobiotic receptor PXR recognizes a range of potentially harmful drugs and endobiotic chemicals but must complex with the nuclear receptor RXRα to control the expression of numerous drug metabolism genes. To date, the structural basis and functional consequences of this interaction have remained unclear. Here we present 2.8-Å-resolution crystal structures of the heterodimeric complex formed between the ligand-binding domains of human PXR and RXRα. These structures establish that PXR and RXRα form a heterotetramer unprecedented in the nuclear receptor family of ligand-regulated transcription factors. We further show that both PXR and RXRα bind to the transcriptional coregulator SRC-1 with higher affinity when they are part of the PXR/RXRα heterotetramer complex than they do when each ligand-binding domain is examined alone. Furthermore, we purify the full-length forms of each receptor from recombinant bacterial expression systems and characterize their interactions with a range of direct and everted repeat DNA elements. Taken together, these data advance our understanding of PXR, the master regulator of drug metabolism gene expression in humans, in its functional partnership with RXRα.
人核异源生物受体 PXR 识别一系列潜在有害药物和内源性化学物质，但必须与核受体 RXRα 形成复合物，以控制众多药物代谢基因的表达。迄今为止，这种相互作用的结构基础和功能后果仍不清楚。在这里，我们呈现了人 PXR 和 RXRα 的配体结合域形成的异二聚体复合物的 2.8-Å 分辨率晶体结构。这些结构表明，PXR 和 RXRα 形成了一种前所未有的异四聚体，在核受体家族的配体调控转录因子中。我们进一步表明，当 PXR 和 RXRα 作为 PXR/RXRα 异四聚体复合物的一部分时，它们与转录共激活因子 SRC-1 的结合亲和力高于每个配体结合域单独检测时的结合亲和力。此外，我们从重组细菌表达系统中纯化了每个受体的全长形式，并表征了它们与一系列直接和倒重复 DNA 元件的相互作用。总之，这些数据增进了我们对 PXR 的理解，PXR 是人类药物代谢基因表达的主要调节剂，它与 RXRα 形成功能伙伴关系。
