Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB.
Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB.
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DOI：
10.1038/s41467-022-34892-4
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发表时间：
2022-11-21
影响因子：
16.6
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
--
作者：
Murray, Meghan H.;Valfort, Aurore Cecile;Koelblen, Thomas;Ronin, Celine;Ciesielski, Fabrice;Chatterjee, Arindam;Veerakanellore, Giri Babu;Elgendy, Bahaa;Walker, John K.;Hegazy, Lamees;Burris, Thomas P.
核受体REV-ERB在一系列生理过程中起着重要作用。REV-ERB是一种配体依赖性转录抑制因子，血红素是一种生理激动剂。我们目前对配体如何与REV-ERB结合并调节REV-ERB的转录抑制的理解是基于与REV-ERB结合的血红素的结构。然而，卟啉（血红素）类似物已被避免作为合成激动剂的来源，由于血红素结合蛋白和潜在的多效性效应的广泛范围。非卟啉合成激动剂如何结合和调节REV-ERB尚未确定。在这里，我们描述了一种高亲和力的合成REV-ERB激动剂，STL 1267，并描述了其结合REV-ERB的机制，以及它招募转录辅阻遏物的方法，这两者都是独特的，不同于血红素结合的REV-ERB。核受体REV-ERBα是血红素的受体，在一系列生理过程中发挥作用。在这里，作者提供了REV-ERB与合成非卟啉配体结合的第一种结构，定义了血红素结合方式的关键机制差异。
The nuclear receptor REV-ERB plays an important role in a range of physiological processes. REV-ERB behaves as a ligand-dependent transcriptional repressor and heme has been identified as a physiological agonist. Our current understanding of how ligands bind to and regulate transcriptional repression by REV-ERB is based on the structure of heme bound to REV-ERB. However, porphyrin (heme) analogues have been avoided as a source of synthetic agonists due to the wide range of heme binding proteins and potential pleotropic effects. How non-porphyrin synthetic agonists bind to and regulate REV-ERB has not yet been defined. Here, we characterize a high affinity synthetic REV-ERB agonist, STL1267, and describe its mechanism of binding to REV-ERB as well as the method by which it recruits transcriptional corepressor both of which are unique and distinct from that of heme-bound REV-ERB. The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.
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影响因子：
4
作者：
Grant, Daniel;Yin, Lei;Zuercher, William J.
通讯作者：
Zuercher, William J.
影响因子：
4
作者：
Meng QJ;McMaster A;Beesley S;Lu WQ;Gibbs J;Parks D;Collins J;Farrow S;Donn R;Ray D;Loudon A
通讯作者：
Loudon A
影响因子：
--
作者：
Burris TP;Busby SA;Griffin PR
通讯作者：
Griffin PR
影响因子：
29.4
作者：
Pourcet B;Zecchin M;Ferri L;Beauchamp J;Sitaula S;Billon C;Delhaye S;Vanhoutte J;Mayeuf-Louchart A;Thorel Q;Haas JT;Eeckhoute J;Dombrowicz D;Duhem C;Boulinguiez A;Lancel S;Sebti Y;Burris TP;Staels B;Duez HM
通讯作者：
Duez HM
影响因子：
9.8
作者：
Pardee KI;Xu X;Reinking J;Schuetz A;Dong A;Liu S;Zhang R;Tiefenbach J;Lajoie G;Plotnikov AN;Botchkarev A;Krause HM;Edwards A
通讯作者：
Edwards A