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.
Figure 1.
Fig. 1. The structure of actinomycin D.
Figure 5.
Fig. 5. Space-filling structures of the classic
ActD/5'-(GC)/(CG)-5' complex (Left) and the
ActD/5'-(GGC)/(CCG)-5' (Right) complex. The color scheme used is
the same as that in Fig. 4. The coordinates for the
ActD/5'-(GC)/(CG)-5' complex are taken from Liu et al. (6). The
views into the minor groove are shown in Top, whereas the
down-to-the-helical views are shown in Bottom. The extra
hydrophobic contact region between the ActD and DNA in the minor
groove is indicated by a blue arrow.
