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Insights into RNA binding by the anticancer drug cisplatin from the crystal structure of cisplatin-modified ribosome

Lookup NU author(s): Dr Sergey MelnikovORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

Abstract

© 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.

Publication metadata

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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Funding

Funder referenceFunder name
Howard Hughes Medical Institute and U.S. National Institutes of Health [GM022778 to T.A.S.]
Funding for open access charge: Illinois State startup funds (Y.S.P.); Howard Hughes Medical Institute (T.A.S.).
Illinois State startup funds (to Y.S.P.)
U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
U.S. National Institute of General Medical Sciences [P41GM103403 to the Northeastern Collaborative Access Team (NE-CAT) at the Advanced Photon Source (beamline 24-ID)];
U.S. National Institutes of Health [GM022854 to D.S.];

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