Nucleic Acids Research, Vol 26, Issue 12 3001-3005, Copyright © 1998 by Oxford University Press
R Dutta, YG Gao, W Priebe and AH Wang
2'-Bromo-4'-epi-daunorubicin (alpha-manno configuration, denoted WP401) is
a new anthracycline drug that exhibits promising activity toward
multidrug-resistant cancer cells. We carried out X-ray diffraction analyses
of the complexes formed in the presence of formaldehyde between WP401 and
two DNA hexamers, TGGCCG and CGG[br5C]CG. The two complexes crystallized in
different crystal lattices with respective crystal data of space group
P4322, a = b = 37.20 A, c = 70.53 A and space group P43212, a = b = 37.23
A, c = 61. 96 A. These new crystal forms are different from the P41212 form
of other daunorubicin/doxorubicin complexes studied previously. The refined
crystal structures at approximately 2.0 A resolution revealed that the
entire 2:1 drug-DNA complex is in the asymmetrical unit. Two WP401 drug
molecules bind to the duplex, with the aglycones intercalated between the
CpG or TpG steps and their modified daunosamines in the minor groove. As
observed earlier, in the presence of formaldehyde, WP401 more readily forms
a covalent adduct with (C/T)GG*:CCG than with (C/T)GC:G*CG (G* is the
crosslink site), the opposite of what is seen for daunorubicin and
doxorubicin. Surprisingly, the two T-G mismatched base pairs in the
WP401-TGGCCG complex adopt the reverse Watson-Crick conformation, instead
of the wobble conformation. The unusual T-G reverse Watson-Crick
conformation may be required in order to maintain favorable stacking
interactions between the base pair and the aglycone of WP401. Our results
show that chemical modifications like bromo or iodo substitution on
anthracycline drugs have significant effects on their DNA binding
properties.
ARTICLES
Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes
Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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