Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.
Structures of human TR4LBD-JAZF1 and TR4DBD-DNA complexes reveal the molecular basis of transcriptional regulation.
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人类TR4LBD-JAZF1和TR4DBD-DNA复合物的结构揭示了转录调控的分子基础
DOI：
10.1093/nar/gkac1259
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发表时间：
2023-02-22
影响因子：
14.9
通讯作者：
Chen, Zhongzhou
中科院分区：
文献类型：
--
作者：
Liu, Yunlong;Ma, Lulu;Li, Min;Tian, Zizi;Yang, Meiting;Wu, Xi;Wang, Xue;Shang, Guohui;Xie, Mengjia;Chen, Yiyun;Liu, Xin;Jiang, Lun;Wu, Wei;Xu, Chaoqun;Xia, Liqun;Li, Gonghui;Dai, Shaodong;Chen, Zhongzhou
睾丸核受体4(TR4)调节基因的转录激活，在许多疾病中发挥重要作用。TR4对靶基因的调控包括通过DNA结合域(DBD)与DNA分子直接相互作用以及通过配体结合域(LBD)招募辅助调节因子。然而，他们的监管机制尚不清楚。在这里，我们报道了TR4DBD、TR4DBD-DNA络合物和TR4LBD-JAZF1络合物的高分辨晶体结构。对于DNA识别，多种因素起作用，并且在TR4和靶基因之间发现了特定的相互选择性。共激活子SRC-1和CREBBP可以结合在原来由TR4激活功能区2(AF-2)占据的TR4的界面上，但JAZF1通过一种新的机制抑制了结合。JAZF1结合到一个未知的Tr4表面，稳定了核受体家族中从未报道过的α13螺旋。此外，肿瘤相关突变分别在体外和体内影响TR4的相互作用和转录激活。总体而言，我们的结果突出了DNA识别的关键作用和JAZF1如何增强自身抑制的构象并影响TR4转录激活的新机制，为包括糖尿病和癌症在内的各种疾病的药物设计奠定了重要的结构基础。
Testicular nuclear receptor 4 (TR4) modulates the transcriptional activation of genes and plays important roles in many diseases. The regulation of TR4 on target genes involves direct interactions with DNA molecules via the DNA-binding domain (DBD) and recruitment of coregulators by the ligand-binding domain (LBD). However, their regulatory mechanisms are unclear. Here, we report high-resolution crystal structures of TR4DBD, TR4DBD–DNA complexes and the TR4LBD–JAZF1 complex. For DNA recognition, multiple factors come into play, and a specific mutual selectivity between TR4 and target genes is found. The coactivators SRC-1 and CREBBP can bind at the interface of TR4 originally occupied by the TR4 activation function region 2 (AF-2); however, JAZF1 suppresses the binding through a novel mechanism. JAZF1 binds to an unidentified surface of TR4 and stabilizes an α13 helix never reported in the nuclear receptor family. Moreover, the cancer-associated mutations affect the interactions and the transcriptional activation of TR4 in vitro and in vivo, respectively. Overall, our results highlight the crucial role of DNA recognition and a novel mechanism of how JAZF1 reinforces the autorepressed conformation and influences the transcriptional activation of TR4, laying out important structural bases for drug design for a variety of diseases, including diabetes and cancers.
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影响因子：
6.4
作者：
Wang M;Sun Y;Xu J;Lu J;Wang K;Yang DR;Yang G;Li G;Chang C
通讯作者：
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DOI：
10.1073/pnas.2021287118
发表时间：
2021-02-09
影响因子：
11.1
作者：
de Vries RMJM;Meijer FA;Doveston RG;Leijten-van de Gevel IA;Brunsveld L
通讯作者：
Brunsveld L
影响因子：
14.9
作者：
Lavery R;Moakher M;Maddocks JH;Petkeviciute D;Zakrzewska K
通讯作者：
Zakrzewska K
DOI：
10.1073/pnas.91.13.6040
发表时间：
1994-06-21
影响因子：
11.1
作者：
CHANG, CS;DASILVA, SL;BURBACH, JPH
通讯作者：
BURBACH, JPH
影响因子：
8.8
作者：
Bendell, Johanna C.;Javle, Milind;Patnaik, Amita
通讯作者：
Patnaik, Amita