Target structure-based discovery of small molecules that block human p53 and CREB binding protein association
Target structure-based discovery of small molecules that block human p53 and CREB binding protein association
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DOI：
10.1016/j.chembiol.2005.10.014
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Zhou, MM
中科院分区：
文献类型：
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作者：
Sachchidanand;Resnick-Silverman, L;Zhou, MM
人肿瘤抑制因子p53在细胞应激信号下的赖氨酸乙酰化是其作为调节细胞周期停滞、衰老或凋亡的转录因子的功能所必需的。在这里，我们报告的小分子，阻止赖氨酸382-乙酰化p53协会与溴结构域的共激活剂CBP，一个相互作用必不可少的p53诱导的转录的细胞周期抑制剂p21在DNA损伤。这些化学物质是在基于CBP布罗莫结构域/p53-AcK 382结合的结构知识构建的聚焦化学文库的靶结构引导的核磁共振光谱筛选中发现的。结构表征表明，这些化学品通过结合溴结构域的乙酰基-赖氨酸结合位点抑制CBP/p53缔合。基于细胞的功能测定表明，铅化学品可以调节p53的稳定性和功能，以响应DNA损伤。
Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage.