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Biopolymers. 2015 Aug;103(8):449-59. doi: 10.1002/bip.22591.

Novel insights on the DNA interaction of calicheamicin γ₁(I).

Author information

  • 1Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.
  • 2Chemistry Department, Yale University, 225 Prospect Street, New Haven, CT, 06511.

Abstract

Calicheamicin γ1(I) (Cal) is a unique molecule in which a DNA binding motif (aryl-tetrasaccharide) is linked to a DNA cleaving moiety (calicheamicinone). The hallmark of this natural product rests in the impressive optimization of these two mechanisms leading to a drug that is extremely efficient in cleaving DNA at well-defined sites. However, the relative contributions of these two structurally distinct domains to the overall process have not been fully elucidated yet. Here, we used different experimental approaches to better dissect the role of the aryl-tetrasaccharide and the enediyne moieties in the DNA sequence selective binding step as well as the in the cleavage reaction. Our results highlight the remarkable cooperation of the two components in producing an amazing molecular machine. The herein presented molecular details of this concerted mechanism of action can be further applied to rationally design more druggable compounds.

KEYWORDS:

DNA binding; DNA cleavage; calicheamicin g1I

PMID:
25411012
DOI:
10.1002/bip.22591
[PubMed - indexed for MEDLINE]
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