Abstract
THE success of cisplatin in cancer chemotherapy derives from its ability to crosslink DNA and alter the structure. Most cisplatiná¤-DNA adducts are intrastrand d(GpG) and d(ApG) crosslinks1, which unwind and bend the duplex to facilitate the binding of proteins that contain one or more high-mobility-group (HMG) domains2. When HMG-domain proteins such as HMG1, IXR (intrastrand-crosslink recognition) protein from yeast, or human upstream-binding factor (hUBF) bind cisplatin intrastrand crosslinks, they can be diverted from their natural binding sites on the genome and shield the adducts from excision repair3-5. These activities sensitize cells to cisplatin and contribute to its cytotoxic properties. Crystallographic information about the structure of cisplatiná¤-DNA adducts has been limited to short single-stranded deoxyoligonucleotides such ascis[Pt(NH3)2{d(pGpG)}]6-8. Here we describe the X-ray structure at 2.6 Å resolution of a double-stranded DNA dodecamer containing this adduct. Our information provides, to our knowledge, the first crystallographic look at a platinated DNA duplex and should help the design of new platinum and other metal crosslinking antitumour drug candidates. Moreover, the structure reveals a unique fusion of A- and B-type DNA segments that could be of more general importance.
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Takahara, P., Rosenzweig, A., Frederick, C. et al. Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature 377, 649–652 (1995). https://doi.org/10.1038/377649a0
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DOI: https://doi.org/10.1038/377649a0
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