BRCT 四肽结合相互作用的结构特征。
Structural characterization of BRCT-tetrapeptide binding interactions.
机构信息
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, 77555, USA.
出版信息
Biochem Biophys Res Commun. 2010 Mar 5;393(2):207-10. doi: 10.1016/j.bbrc.2010.01.098. Epub 2010 Feb 1.
Abstract
BRCT(BRCA1) plays a major role in DNA repair pathway, and does so by recognizing the conserved sequence pSXXF in its target proteins. Remarkably, tetrapeptides containing pSXXF motif bind with high specificity and micromolar affinity. Here, we have characterized the binding interactions of pSXXF tetrapeptides using NMR spectroscopy and calorimetry. We show that BRCT is dynamic and becomes structured on binding, that pSer and Phe residues dictate overall binding, and that the binding affinities of the tetrapeptides are intimately linked to structural and dynamic changes both in the BRCT(BRCA1) and tetrapeptides. These results provide critical insights for designing high-affinity BRCT(BRCA1) inhibitors.
摘要
BRCT（BRCA1）在 DNA 修复途径中发挥着重要作用，它通过识别其靶蛋白中的保守序列 pSXXF 来实现这一功能。值得注意的是，含有 pSXXF 模体的四肽以高特异性和微摩尔亲和力结合。在这里，我们使用 NMR 光谱和量热法研究了 pSXXF 四肽的结合相互作用。我们表明 BRCT 是动态的，在结合时变得结构化，pSer 和 Phe 残基决定整体结合，并且四肽的结合亲和力与 BRCT（BRCA1）和四肽中的结构和动态变化密切相关。这些结果为设计高亲和力 BRCT（BRCA1）抑制剂提供了重要的见解。
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