3M4O

RNA polymerase II elongation complex B

Summary for 3M4O

• Entry DOI: 10.2210/pdb3m4o/pdb
• Related: 1R9T 2E2H 3CO3 3M3Y
• Descriptor: DNA-directed RNA polymerase II subunit RPB1, DNA-directed RNA polymerases I, II, and III subunit RPABC4, RNA (5'-R(*AP*UP*GP*GP*AP*GP*AP*GP*GP*A)-3'), ... (16 entities in total)
• Functional Keywords: transcription, mrna, multiprotein complex, molecular machine, dna, dna damage, cancer, platinum drug, dna-binding, dna-directed rna polymerase, isopeptide bond, magnesium, metal-binding, nucleotidyltransferase, nucleus, phosphoprotein, transferase, ubl conjugation, zinc, zinc-finger, polymorphism, cytoplasm, dna repair, transferase-dna-rna hybrid complex, transferase/dna-rna hybrid
• Biological source: Saccharomyces cerevisiae (brewer's yeast,lager beer yeast,yeast); More
• Cellular location: Nucleus: P04050 P08518 P16370 P20434 P20436 P27999 P38902; Nucleus, nucleolus: P40422 P22139; Cytoplasm: P20435
• Total number of polymer chains: 13
• Total formula weight: 486554.54

Authors

Wang, D.,Zhu, G.,Huang, X.,Lippard, S.J. (deposition date: 2010-03-11, release date: 2010-05-12, Last modification date: 2024-10-09)

Primary citation

Wang, D.,Zhu, G.,Huang, X.,Lippard, S.J.
X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct.
Proc.Natl.Acad.Sci.USA, 107:9584-9589, 2010

PubMed Abstract: 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.

PubMed: 20448203
DOI: 10.1073/pnas.1002565107

Experimental method

X-RAY DIFFRACTION (3.57 Å)