Nucleic Acids Research, Vol 24, Issue 24 4882-4889, Copyright © 1996 by Oxford University Press
GR Clark, CJ Squire, EJ Gray, W Leupin and S Neidle
An analogue of the DNA binding compound Hoechst 33258, which has the para
hydroxyl group altered to be at the meta position, together with the
replacement of one benzimidazole group by pyridylimidazole, has been
cocrystallized with the dodecanucleotide sequence d(CGCGAATTCGCG)2. The
X-ray structure has been determined at 2.2 A resolution and refined to an R
factor of 20.1%. The ligand binds in the minor groove at the sequence
5'-AATTC with the bulky piperazine group extending over the CxG base pair.
This binding is stabilised by hydrogen bonding and numerous close van der
Waals contacts to the surface of the groove walls. The meta-hydroxyl group
was found in two distinct orientations, neither of which participates in
direct hydrogen bonds to the exocyclic amino group of a guanine base. The
conformation of the drug differs from that found previously in other X-ray
structures of Hoechst 33258-DNA complexes. There is significant variation
between the minor groove widths in the complexes of Hoechst 33258 and the
meta-hydroxyl derivative as a result of these conformational differences.
Reasons are discussed for the inability of this derivative to actively
recognise guanine.
ARTICLES
Designer DNA-binding drugs: the crystal structure of a meta-hydroxy analogue of Hoechst 33258 bound to d(CGCGAATTCGCG)2
The CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, UK.
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