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首页> 外文期刊>Biochemistry >The Structural Basis of Pregnane X Receptor Binding Promiscuity
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The Structural Basis of Pregnane X Receptor Binding Promiscuity

机译：孕烷X受体结合混杂的结构基础

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The steroid and xenobiotic-responsive human pregnane X receptor (PXR) binds a broad range ofnstructurally diverse compounds. The structures of the apo and ligand-bound forms of PXRare very similar, inncontrast to most promiscuous proteins that generally adapt their shape to different ligands. We investigatednthe structural origins of PXR’s recognition promiscuity using computational solvent mapping, a techniquendeveloped for the identification and characterization of hot spots, i.e., regions of the protein surface that arenmajor contributors to the binding free energy. Results reveal that the smooth and nearly spherical binding sitenof PXR has a well-defined hot spot structure, with four hot spots located on four different sides of the pocketnand a fifth close to its center. Three of these hot spots are already present in the ligand-free protein. The mostnimportant hot spot is defined by three structurally and sequentially conserved residues, W299, F288, andnY306. This largely hydrophobic site is not very specific and interacts with all known PXR ligands. Dependingnon their sizes and shapes, individual PXR ligands extend into two, three, or four more hot spot regions. Thenlarge number of potential arrangements within the binding site explains why PXR is able to accommodate anlarge variety of compounds. All five hot spots include at least one important residue, which is conserved in allnmammalian PXRs, suggesting that the hot spot locations have remained largely invariant during mammaliannevolution. The same side chains also show a high level of structural conservation across hPXR structures.nHowever, each of the hPXR hot spots also includes residues with moveable side chains, further increasing thensize variation in ligands that PXR can bind. Results also suggest a unique signal transduction mechanismnbetween the PXR homodimerization interface and its coactivator binding site.
机译：类固醇和异种生物应答的人类孕烷X受体（PXR）结合多种结构上不同的化合物。载脂蛋白和配体结合形式的PXR的结构非常相似，与大多数混杂蛋白质不同，后者通常使它们的形状适应不同的配体。我们使用计算溶剂作图法研究了PXR识别混杂的结构起源，这是一种用于识别和表征热点的技术，该热点即对结合自由能不重要的蛋白质表面区域。结果表明，PXR的光滑且接近球形的结合位点具有明确的热点结构，其中四个热点位于袋的四个不同侧面，而第五个热点位于其中心附近。这些热点中的三个已经存在于无配体蛋白中。最重要的热点由三个结构和顺序保守的残基W299，F288和nY306定义。该很大程度上疏水的位点不是很特异性，并且与所有已知的PXR配体相互作用。取决于它们的大小和形状，单独的PXR配体延伸到另外两个，三个或四个热点区域。然后，结合位点内的大量潜在排列说明了PXR为何能够容纳多种化合物。所有五个热点均包括至少一个重要残基，该残基在所有哺乳动物PXR中均保守，这表明在哺乳动物进化过程中，热点的位置在很大程度上保持不变。相同的侧链在hPXR结构上也显示出高水平的结构保守性。然而，每个hPXR热点还包括带有可移动侧链的残基，从而进一步增加了PXR可以结合的配体的大小变化。结果还表明，PXR均二聚化界面与其共激活因子结合位点之间存在独特的信号转导机制。

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