title: Insights into RNA binding by the anticancer drug cisplatin from the crystal structure of cisplatin-modified ribosome.
abstract: 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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Melnikov
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Dieter
authors.initials: D
authors.lastname: Söll
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA Department of Chemistry, Yale University, New Haven, CT 06520, USA Howard Hughes Medical Institute at Yale University, New Haven, CT 06520, USA thomas.steitz@yale.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Steitz
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60607, USA yuryp@uic.edu.
authors.forename: Yury S
authors.identifier: 0000-0002-5064-0327
authors.initials: YS
authors.lastname: Polikanov
mesh_terms: D000225:Adenine / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism; D003374:Coumarins / Q000737:chemistry; D018360:Crystallography, X-Ray; D006147:Guanine / Q000737:chemistry; D008958:Models, Molecular; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry; D012335:RNA, Ribosomal / Q000737:chemistry* / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D003374:Coumarins; D019384:Nucleic Acid Synthesis Inhibitors; D012335:RNA, Ribosomal; C031379:amicoumacin A; D006147:Guanine; D000225:Adenine; D002945:Cisplatin