Recognition of bulged DNA by a neocarzinostatin product via an induced fit mechanism.
The binding of the wedge-shaped isostructural analogue of the biradical species of the chromphore of antitumor antibiotic neocarzinostatin to sequence-specific bulged DNAs results in alterations in ellipticity of the DNAs. Circular dichroism (CD) spectroscopic results suggest that the drug specifically recognizes bulges of DNA via a combination of conformational selection and induced fit, not by binding to a preorganized site. Analysis of circular dichroism spectra indicates that the degree of induced fit observed is primarily a consequence of optimising van der Waals contacts with the walls of the bulge cavity. The effective recognition of the bulge site on duplex DNA appears to depend to a significant extent on the bent groove space being flexible enough to be able to adopt the geometrically optimal conformation compatible with the wedge-shaped drug molecule, rather than involving 'lock and key' recognition. The spectroscopic results indicate a change of DNA conformation, consistent with an allosteric binding model. Spectroscopic studies with various bulged DNAs also reveal that the binding strength directly correlates with the stability of the bulge structures.
Yang
Catherine F
CF
Department of Chemistry, Rowan University, Glassboro, NJ 08028, USA. yang@rowan.edu
Jackson
Patricia J
PJ
Xi
Zhen
Z
Goldberg
Irving H
IH
D000495:Allosteric Site; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D053281:Enediynes; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D009353:Zinostatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D019384:Nucleic Acid Synthesis Inhibitors; D009838:Oligodeoxyribonucleotides; C032372:neocarzinostatin chromophore; D004247:DNA; D009353:Zinostatin