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dc.contributor.authorZhu, Guangyu
dc.contributor.authorLippard, Stephen J.
dc.contributor.authorWang, Dong
dc.contributor.authorHuang, Xuhui
dc.date.accessioned2013-11-15T20:28:15Z
dc.date.available2013-11-15T20:28:15Z
dc.date.issued2010-05
dc.date.submitted2010-03
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/82147
dc.description.abstractDNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (Grant CA034992)en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1002565107en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleX-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adducten_US
dc.typeArticleen_US
dc.identifier.citationWang, D., G. Zhu, X. Huang, and S. J. Lippard. “X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct.” Proceedings of the National Academy of Sciences 107, no. 21 (May 25, 2010): 9584-9589.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistryen_US
dc.contributor.mitauthorZhu, Guangyuen_US
dc.contributor.mitauthorLippard, Stephen J.en_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsWang, D.; Zhu, G.; Huang, X.; Lippard, S. J.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-2693-4982
mit.licensePUBLISHER_POLICYen_US


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