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Lookup NU author(s): Dr Sergey MelnikovORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2016 The Author(s).Cisplatin is a widely prescribed anticancer drug, which triggers cell death by covalent binding to a broad range of biological molecules. Among cisplatin targets, cellular RNAs remain the most poorly characterized molecules. Although cisplatin was shown to inactivate essential RNAs, including ribosomal, spliceosomal and telomeric RNAs, cisplatin binding sites in most RNA molecules are unknown, and therefore it remains challenging to study how modifications of RNA by cisplatin contributes to its toxicity. Here we report a 2.6Å-resolution X-ray structure of cisplatin-modified 70S ribosome, which describes cisplatin binding to the ribosome and provides the first nearly atomic model of cisplatin-RNA complex. We observe nine cisplatin molecules bound to the ribosome and reveal consensus structural features of the cisplatin-binding sites. Two of the cisplatin molecules modify conserved functional centers of the ribosome-the mRNA-channel and the GTPase center. In the mRNA-channel, cisplatin intercalates between the ribosome and the messenger RNA, suggesting that the observed inhibition of protein synthesis by cisplatin is caused by impaired mRNA-translocation. Our structure provides an insight into RNA targeting and inhibition by cisplatin, which can help predict cisplatin-binding sites in other cellular RNAs and design studies to elucidate a link between RNA modifications by cisplatin and cisplatin toxicity.
Author(s): Melnikov SV, Soll D, Steitz TA, Polikanov YS
Publication type: Article
Publication status: Published
Journal: Nucleic Acids Research
Year: 2016
Volume: 44
Issue: 10
Pages: 4978-4987
Print publication date: 02/06/2016
Online publication date: 13/04/2016
Acceptance date: 02/04/2016
Date deposited: 20/05/2020
ISSN (print): 0305-1048
ISSN (electronic): 1362-4962
Publisher: Oxford University Press
URL: https://doi.org/10.1093/nar/gkw246
DOI: 10.1093/nar/gkw246
PubMed id: 27079977
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