Nucleic Acids Research, 2002, Vol. 30, No. 22 4881-4891
© 2002 Oxford University Press
Solution structure of the hydroperoxide of Co(III) phleomycin complexed with d(CCAGGCCTGG)2: evidence for binding by partial intercalation
1 Department of Chemistry and 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA, 3 Merck Research Laboratory, PO Box 2000, Rahway, NJ 07065-0900, USA and 4 Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
*To whom correspondence should be addressed at Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Tel: +1 617 253 1814; Fax: +1 617 258 7247; Email: stubbe{at}mit.edu
Present addresses:
Dana E. Vanderwall, Glaxo Wellcome, 5 Moore Drive, Research Triangle Park, NC 27709, USA
John W. Kozarich, Activx, North Torrey Pines Road, La Jolla, CA 92037, USA
The bleomycins (BLMs) are natural products that in the presence of iron and oxygen bind to and cause single-strand and double-strand cleavage of DNA. The mode(s) of binding of the FeBLMs that leads to sequence-specific cleavage at pyrimidines 3' to guanines and chemical-specific cleavage at the C-4' H of the deoxyribose of the pyrimidine has remained controversial. 2D NMR studies using the hydroperoxide of CoBLM (HOO-CoBLM) have demonstrated that its bithiazole tail binds by partial intercalation to duplex DNA. Studies with ZnBLM demonstrate that the bithiazole tail binds in the minor groove. Phleomycins (PLMs) are BLM analogs in which the penultimate thiazolium ring of the bithiazole tail is reduced. The disruption of planarity of this ring and the similarities between FePLM- and FeBLM-mediated DNA cleavage have led Hecht and co-workers to conclude that a partial intercalative mode of binding is not feasible. The interaction of HOO-CoPLM with d(CCAGGCCTGG)2 has therefore been investigated. Binding studies indicate a single site with a Kd of 16 µM, 100-fold greater than HOO-CoBLM for the same site. 2D NMR methods and molecular modeling using NMR-derived restraints have led to a structural model of HOO-CoPLM complexed to d(CCAGGCCTGG)2. The model reveals a partial intercalative mode of binding and the basis for sequence specificity of binding and chemical specificity of cleavage. The importance of the bithiazoles and the partial intercalative mode of binding in the double-strand cleavage of DNA is discussed.
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  J. Chen, M. K. Ghorai, G. Kenney, and J. Stubbe Mechanistic studies on bleomycin-mediated DNA damage: multiple binding modes can result in double-stranded DNA cleavage Nucleic Acids Res., June 1, 2008; 36(11): 3781 - 3790. [Abstract] [Full Text] [PDF]
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