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PDBsum entry 3m4o
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Transferase/DNA-RNA hybrid
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PDB id
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3m4o
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Contents |
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1395 a.a.
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1106 a.a.
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266 a.a.
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214 a.a.
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84 a.a.
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133 a.a.
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119 a.a.
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65 a.a.
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114 a.a.
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46 a.a.
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References listed in PDB file
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Key reference
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Title
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X-Ray structure and mechanism of RNA polymerase ii stalled at an antineoplastic monofunctional platinum-Dna adduct.
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Authors
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D.Wang,
G.Zhu,
X.Huang,
S.J.Lippard.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
9584-9589.
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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DNA 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.
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