Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule.
Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule.
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DOI：
10.3389/fmolb.2022.823195
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发表时间：
2022
影响因子：
5
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中科院分区：
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恢复p53肿瘤抑制因子用于个体化癌症治疗是一种很有前途的治疗策略。然而，一些高亲和力的MDM2抑制剂在临床试验中显示出明显的副作用。因此，阐明具有替代功能原理的p53再激活分子的作用分子机制是至关重要的。在这里，我们报告了一种新的p53再激活的变构机制，通过靶向p53 n端促进p53/MDM2（小鼠双分钟2）和p53/MDM4相互作用的抑制。通过生化分析和分子对接，我们确定了两个p53再激活分子RITA （p53再激活和诱导肿瘤细胞凋亡）和原卟啉IX （PpIX）的结合位点。离子迁移-质谱分析显示，RITA与丝氨酸33和丝氨酸37的结合诱导了p53的变构位移，从而屏蔽了p53的MDM2结合残基，阻止了它与MDM2和MDM4的相互作用。我们的研究结果指出了阻断p53与MDM2和MDM4相互作用的另一种机制，并可能为开发p53/MDM2和p53/MDM4相互作用的新型变构抑制剂铺平道路。
Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.