Structural basis for inhibition of the MDM2:p53 interaction by an optimized MDM2-binding peptide selected with mRNA display.
Structural basis for inhibition of the MDM2:p53 interaction by an optimized MDM2-binding peptide selected with mRNA display.
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DOI：
10.1371/journal.pone.0109163
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yanagawa H
中科院分区：
文献类型：
--
作者：
Nagata T;Shirakawa K;Kobayashi N;Shiheido H;Tabata N;Sakuma-Yonemura Y;Horisawa K;Katahira M;Doi N;Yanagawa H
癌蛋白MDM2与肿瘤抑制蛋白p53结合并抑制其抗癌活性，从而促进肿瘤细胞生长和肿瘤存活。据报道，p53:MDM2 相互作用的废除会导致 p53 通路的重新激活和肿瘤细胞增殖的抑制。我们最近通过 mRNA 展示对 MDM2 结合肽进行了严格的选择，并鉴定了一种最佳的 12 聚体肽 (PRFWEYWLRLME)，命名为 MDM2 抑制肽 (MIP)，与已知的肽相比，它对 MDM2（及其同源物 MDMX）表现出更高的亲和力和更高的肿瘤细胞增殖抑制活性。在这里，我们确定了 MIP-MDM2 融合蛋白的 NMR 溶液结构，以阐明 MIP 与 MDM2 紧密结合的结构基础。 MIP 的从 Phe3 到 Met11 的区域形成单个 α 螺旋，该螺旋比其他 MDM2 结合肽的螺旋更长。 MIP 共享一个保守的 Phe3-Trp7-Leu10 三联体，其侧链面向并适合 MDM2 的疏水口袋。此外，围绕 MDM2 疏水袋的疏水表面斑块被暴露于溶剂的 MIP 残基、Trp4、Tyr6 和 Met11 覆盖。它们的疏水相互作用扩展了两个分子的界面并有助于强结合。观察到的 MIP 潜在的 MDM2 抑制活性源于其扩大的结合界面。本研究中获得的结构信息为合理设计MDM2:p53结合的强抑制剂提供了路线图。
The oncoprotein MDM2 binds to tumor suppressor protein p53 and inhibits its anticancer activity, which leads to promotion of tumor cell growth and tumor survival. Abrogation of the p53:MDM2 interaction reportedly results in reactivation of the p53 pathway and inhibition of tumor cell proliferation. We recently performed rigorous selection of MDM2-binding peptides by means of mRNA display and identified an optimal 12-mer peptide (PRFWEYWLRLME), named MDM2 Inhibitory Peptide (MIP), which shows higher affinity for MDM2 (and also its homolog, MDMX) and higher tumor cell proliferation suppression activity than known peptides. Here we determined the NMR solution structure of a MIP-MDM2 fusion protein to elucidate the structural basis of the tight binding of MIP to MDM2. A region spanning from Phe3 to Met11 of MIP forms a single α-helix, which is longer than those of the other MDM2-binding peptides. MIP shares a conserved Phe3-Trp7-Leu10 triad, whose side chains are oriented towards and fit into the hydrophobic pockets of MDM2. Additionally, hydrophobic surface patches that surround the hydrophobic pockets of MDM2 are covered by solvent-exposed MIP residues, Trp4, Tyr6, and Met11. Their hydrophobic interactions extend the interface of the two molecules and contribute to the strong binding. The potential MDM2 inhibition activity observed for MIP turned out to originate from its enlarged binding interface. The structural information obtained in the present study provides a road map for the rational design of strong inhibitors of MDM2:p53 binding.
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影响因子：
2.9
作者：
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