期刊
PROTEIN SCIENCE
卷 19, 期 12, 页码 2267-2278出版社
WILEY
DOI: 10.1002/pro.507
关键词
protein; stability; alkylation; p53; DNA; binding
资金
- Medical Research Council
- EU
- Medical Research Council [MC_U105474168] Funding Source: researchfish
- MRC [MC_U105474168] Funding Source: UKRI
Oncogenic mutations inactivate the tumor suppressor p53 by lowering its stability or by weakening its binding to DNA Alkylating agents that reactivate mutant p53 are currently being explored for cancer therapy We have discovered ligands containing an alpha,beta-unsaturated double bond, characteristic of Michael acceptors, that bind covalently to generic cysteine sites in the p53 core domain They raised the melting temperature of the core domain of wild-type p53 and the hotspot mutants R175H, Y220C, G245S, R249S, and R282 by up to 3 degrees C Analysis of the relative reactivity of the cysteines in p53 by mass spectrometry found that C124 and C141 react first, followed by C135, C182, and C277, and eventually C176 and C275 Post-translational modifications of cysteines are known to be involved in regulation of other transcription factors Modification of C277, which sits on the DNA-binding surface, may, for example, play a role in regulating p53 activity in cells in response to environmental cues We found that the modifications progressively reduced DNA-binding activity of full-length p53 In light of these results, it is likely that the anticancer activity of the alkylating drugs works via a nontranscriptional activity of p53
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据