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DOI | 10.1038/s41467-018-06390-z |
A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin | |
Menchon, Gregory1; Prota, Andrea E.1; Lucena-Agell, Daniel2; Bucher, Pascal3; Jansen, Rolf4; Irschik, Herbert4; Mueller, Rolf5,6; Paterson, Ian7; Diaz, J. Fernando2; Altmann, Karl-Heinz3; Steinmetz, Michel O.1,8 | |
2018-05-29 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | Switzerland; Spain; Germany; England |
英文摘要 | Microtubule-targeting agents (MTAs) like taxol and vinblastine are among the most successful chemotherapeutic drugs against cancer. Here, we describe a fluorescence anisotropy-based assay that specifically probes for ligands targeting the recently discovered maytansine site of tubulin. Using this assay, we have determined the dissociation constants of known maytansine site ligands, including the pharmacologically active degradation product of the clinical antibody-drug conjugate trastuzumab emtansine. In addition, we discovered that the two natural products spongistatin-1 and disorazole Z with established cellular potency bind to the maytansine site on beta-tubulin. The high-resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of an additional sub-site adjacent to the pocket shared by all maytansine-site ligands, which could be exploitable as a distinct, separate target site for small molecules. Our study provides a basis for the discovery and development of next-generation MTAs for the treatment of cancer. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000433298500007 |
WOS关键词 | BINDING SITE ; MICROTUBULES ; METABOLITES ; VALIDATION ; RHIZOXIN ; DYNAMICS ; CANCER |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204011 |
专题 | 资源环境科学 |
作者单位 | 1.Paul Scherrer Inst, Div Biol & Chem, Lab Biomol Res, CH-5232 Villigen, Switzerland; 2.CSIC, Ctr Invest Biol, Chem & Phys Biol, Madrid 28040, Spain; 3.ETH, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland; 4.Helmholtz Zentrum Infekt Forsch, Abt Mikrobielle Wirkstoffe, D-38124 Braunschweig, Germany; 5.Saarland Univ, Helmholtz Inst Pharmaceut Res Saarland, Helmholtz Ctr Infect Res, Dept Microbial Nat Prod, D-66123 Saarbrucken, Germany; 6.Saarland Univ, Helmholtz Inst Pharmaceut Res Saarland, Helmholtz Ctr Infect Res, Dept Pharm, D-66123 Saarbrucken, Germany; 7.Univ Cambridge, Univ Chem Lab, Cambridge CB2 1EW, England; 8.Univ Basel, Biozentrum, CH-4056 Basel, Switzerland |
推荐引用方式 GB/T 7714 | Menchon, Gregory,Prota, Andrea E.,Lucena-Agell, Daniel,et al. A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Menchon, Gregory.,Prota, Andrea E..,Lucena-Agell, Daniel.,Bucher, Pascal.,Jansen, Rolf.,...&Steinmetz, Michel O..(2018).A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.NATURE COMMUNICATIONS,9. |
MLA | Menchon, Gregory,et al."A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin".NATURE COMMUNICATIONS 9(2018). |
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