Premium
Novel insights on the DNA interaction of calicheamicin γ 1 I
Author(s) -
Sissi Claudia,
Moro Stefano,
Crothers Donald M.
Publication year - 2015
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22591
Subject(s) - calicheamicin , enediyne , chemistry , dna , stereochemistry , tetrasaccharide , moiety , druggability , combinatorial chemistry , natural product , computational biology , biochemistry , genetics , biology , polysaccharide , antibody , gene
Calicheamicin γ 1 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. © 2014 Wiley Periodicals, Inc. Biopolymers 103: 449–459, 2015.