C-terminal substitution of MDM2 interacting peptides modulates binding affinity by distinctive mechanisms.
C-terminal substitution of MDM2 interacting peptides modulates binding affinity by distinctive mechanisms.
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DOI：
10.1371/journal.pone.0024122
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Verma CS
中科院分区：
文献类型：
--
作者：
Brown CJ;Dastidar SG;Quah ST;Lim A;Chia B;Verma CS
MDM2和p53蛋白之间的复合物是一种有前途的癌症治疗药物靶点。p53的残基19 - 26已经被生物化学和结构证明是维持MDM2和p53缔合的最关键区域。氨基酸序列在此范围内的变化明显改变了结合亲和力。令人惊讶的是，与p53肽的该区域相邻的合适取代可以产生紧密结合的肽。所述肽变体可以通过单个残基而不同，所述单个残基在其结构构象上变化很小，但其特征在于其结合亲和力的大差异。在这项研究中，一个12残基片段的p53反式激活结构域（TD）和一个等效的噬菌体优化肽（12/1）的单一C-末端突变的作用进行了系统的分析，以阐明其与MDM 2的N-末端相互作用的机制和热力学差异。实验结果与原子详细的动力学模拟提供了深入了解的原则，管理肽的设计协议方面的蛋白质-蛋白质相互作用和拟肽设计。
The complex between the proteins MDM2 and p53 is a promising drug target for cancer therapy. The residues 19–26 of p53 have been biochemically and structurally demonstrated to be a most critical region to maintain the association of MDM2 and p53. Variation of the amino acid sequence in this range obviously alters the binding affinity. Surprisingly, suitable substitutions contiguous to this region of the p53 peptides can yield tightly binding peptides. The peptide variants may differ by a single residue that vary little in their structural conformations and yet are characterized by large differences in their binding affinities. In this study a systematic analysis into the role of single C-terminal mutations of a 12 residue fragment of the p53 transactivation domain (TD) and an equivalent phage optimized peptide (12/1) were undertaken to elucidate their mechanistic and thermodynamic differences in interacting with the N-terminal of MDM2. The experimental results together with atomistically detailed dynamics simulations provide insight into the principles that govern peptide design protocols with regard to protein-protein interactions and peptidomimetic design.
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影响因子：
3
作者：
Dastidar SG;Lane DP;Verma CS
通讯作者：
Verma CS
影响因子：
4.4
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
4.3
作者：
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通讯作者：
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