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

Melnikov, Sergey V.; Söll, Dieter; Steitz, Thomas A.; Polikanov, Yury S.

doi:10.1093/nar/gkw246

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

Journal Article · Wed Apr 13 00:00:00 EDT 2016 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkw246· OSTI ID:1258691

Melnikov, Sergey V. ^[1]; Söll, Dieter ^[1]; Steitz, Thomas A. ^[1]; ^[2]

Yale Univ., New Haven, CT (United States)
Univ. of Illinois, Chicago, IL (United States)

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. Furthermore, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1258691

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 10 Vol. 44; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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