A molecular switch regulating transcriptional repression and activation of PPARγ
A molecular switch regulating transcriptional repression and activation of PPARγ
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DOI：
10.1038/s41467-020-14750-x
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发表时间：
2020-02-19
影响因子：
16.6
通讯作者：
Kojetin, Douglas J.
中科院分区：
文献类型：
--
作者：
Shang, Jinsai;Mosure, Sarah A.;Kojetin, Douglas J.
核受体（NR）转录因子使用保守的激活功能-2（AF-2）螺旋12机制进行激动剂诱导的共激活因子相互作用和NR转录激活。相反，配体诱导的辅阻遏物依赖NR抑制似乎发生通过结构上不同的机制。我们报告两个晶体结构的过氧化物酶体增殖物激活受体γ（PPAR γ）的反向激动剂/辅抑制剂结合转录抑制构象。阻碍物12从溶剂暴露的活性构象被置换，并占据通过使口袋体积加倍的构象变化而实现的正构配体结合口袋。顺磁弛豫增强（PRE）NMR和化学交联质谱证实了抑制性螺旋12构象。PRE NMR还定义了辅阻遏物选择性反向激动剂T0070907的作用机制，并揭示了脱辅基螺旋12之间的转录活性和抑制性构象交换-支持NR领域的基本假设，即螺旋12之间的转录活性和抑制性构象交换。核受体转录因子的结构研究表明，几乎所有的核受体都有一个保守的螺旋12依赖的转录激活机制。在这里，作者提出了两个晶体结构的过氧化物酶体增殖物激活受体γ（PPAR γ）在一个反向激动剂/辅抑制剂结合的转录抑制构象，其中螺旋12位于正构配体结合口袋，而不是，并讨论机制的影响。
Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPAR gamma) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations. Structural studies of nuclear receptor transcription factors revealed that nearly all nuclear receptors share a conserved helix 12 dependent transcriptional activation mechanism. Here the authors present two crystal structures of peroxisome proliferator-activated receptor gamma (PPAR gamma) in an inverse agonist/corepressor-bound transcriptionally repressive conformation, where helix 12 is located within the orthosteric ligand-binding pocket instead, and discuss mechanistic implications.