LSD1/CoREST Reversible Opening-Closing Dynamics: Discovery of a Nanoscale Clamp for Chromatin and Protein Binding
LSD1/CoREST Reversible Opening-Closing Dynamics: Discovery of a Nanoscale Clamp for Chromatin and Protein Binding
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DOI：
10.1021/bi300068r
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发表时间：
2012-04-17
期刊：
影响因子：
2.9
通讯作者：
Vellore, Nadeem A.
中科院分区：
文献类型：
--
作者：
Baron, Riccardo;Vellore, Nadeem A.
LSD 1与其辅阻遏蛋白CoREST相关，是表观遗传药物的一个非常相关的靶点。假设LSD 1/CoREST作为染色质和蛋白质结合的多对接位点的作用需要显着的分子灵活性，LSD 1/CoREST大幅度构象动力学目前尚不清楚。在这里，分子动力学模拟表明，LSD 1/CoREST复合物在溶液中的功能作为一个可逆的纳米级结合钳。我们表明，H3组蛋白尾部结合口袋是一个潜在的变构网站调节旋转的SWEARS/SANT 2域周围的塔域。因此，靶向该位点并包括受体柔性是未来药物发现的关键策略。
LSD1 associated with its corepressor protein CoREST is an exceptionally relevant target for epigenetic drugs. Hypotheses for the role of LSD1/CoREST as a multidocking site for chromatin and protein binding would require significant molecular flexibility, and LSD1/CoREST large-amplitude conformational dynamics is currently unknown. Here, molecular dynamics simulation reveals that the LSD1/CoREST complex in solution functions as a reversible nanoscale binding clamp. We show that the H3 histone tail binding pocket is a potential allosteric site for regulation of the rotation of SWIRM/SANT2 domains around the Tower domain. Thus, targeting this site and including receptor flexibility are crucial strategies for future drug discovery.