NMR structure of a complex between MDM2 and a small molecule inhibitor
NMR structure of a complex between MDM2 and a small molecule inhibitor
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DOI：
10.1023/b:jnmr.0000048856.84603.9b
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发表时间：
2004-10-01
影响因子：
2.7
通讯作者：
Podlaski, F
中科院分区：
文献类型：
--
作者：
Fry, DC;Emerson, SD;Podlaski, F
MDM2是一种细胞生长过程的调节剂，通过与肿瘤抑制蛋白p53结合并最终抑制其活性。虽然p53通过突变失活在人类癌症中很常见，但相当大比例的肿瘤表达野生型p53。在许多这些病例中，MDM2过度表达，并且相信抑制MDM2活性可以产生治疗益处。因此，我们一直专注于p53-MDM2相互作用作为药物发现计划的基础，并且已经能够开发一系列小分子抑制剂。我们在此报告了MDM2的p53结合域和其中一种抑制剂之间的复合物的高分辨率NMR结构。使用的MDM2形式是人类和非洲爪蟾序列之间的工程杂交，提供了良好的相关性和稳定性的组合。发现该抑制剂与p53的高效肽片段在同一位点结合。该抑制剂能够通过复制通常由氨基酸侧链形成的三个子囊中的相互作用，并利用具有刚性和空间取向的取代基的支架，成功地模拟肽。该结构也提示了修饰抑制剂以增加其效力的机会。
MDM2 is a regulator of cell growth processes that acts by binding to the tumor suppressor protein p53 and ultimately restraining its activity. While inactivation of p53 by mutation is commonly observed in human cancers, a substantial percentage of tumors express wild type p53. In many of these cases, MDM2 is overexpressed, and it is believed that suppression of MDM2 activity could yield therapeutic benefits. Therefore, we have been focusing on the p53-MDM2 interaction as the basis of a drug discovery program and have been able to develop a series of small molecule inhibitors. We herein report a high resolution NMR structure of a complex between the p53-binding domain of MDM2 and one of these inhibitors. The form of MDM2 utilized was an engineered hybrid between the human and Xenopus sequences, which provided a favorable combination of relevancy and stability. The inhibitor is found to bind in the same site as does a highly potent peptide fragment of p53. The inhibitor is able to successfully mimic the peptide by duplicating interactions in three subpockets normally made by amino acid sidechains, and by utilizing a scaffold that presents substituents with rigidity and spatial orientation comparable to that provided by the alpha helical backbone of the peptide. The structure also suggests opportunities for modifying the inhibitor to increase its potency.