Looped out and perpendicular: deformation of Watson-Crick base pair associated with actinomycin D binding

Proc Natl Acad Sci U S A. 2002 May 14;99(10):6625-30. doi: 10.1073/pnas.102580399.

Abstract

Many anticancer drugs interact directly with DNA to exert their biological functions. To date, all noncovalent, intercalating drugs interact with DNA exclusively by inserting their chromophores into base steps to form elongated and unwound duplex structures without disrupting the flanking base pairs. By using actinomycin D (ActD)-5'-GXC/CYG-5' complexes as examples, we have found a rather unusual interaction mode for the intercalated drug; the central Watson-Crick X/Y base pairs are looped out and displaced by the ActD chromophore. The looped-out bases are not disordered but interact perpendicularly with the base/chromophore and form specific H bonds with DNA. Such a complex structure provides intriguing insights into how ligand interacts with DNA and enlarges the repertoires for sequence-specific DNA recognition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Pairing*
  • DNA / chemistry*
  • Dactinomycin / chemistry*
  • Dactinomycin / pharmacology
  • Deuterium Oxide
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Nucleic Acid Conformation / drug effects
  • Nucleic Acid Synthesis Inhibitors / chemistry*
  • Thermodynamics
  • Water

Substances

  • Nucleic Acid Synthesis Inhibitors
  • Water
  • Dactinomycin
  • DNA
  • Deuterium Oxide

Associated data

  • OMIM/1L1V