Nucleic Acids Research Advance Access originally published online on December 1, 2006
Nucleic Acids Research 2006 34(22):6663-6672; doi:10.1093/nar/gkl930
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Nucleic Acids Research, 2006, Vol. 34, No. 22 6663-6672
© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
X-ray crystallographic study of DNA duplex cross-linking: simultaneous binding to two d(CGTACG)2 molecules by a bis(9-aminoacridine-4-carboxamide) derivative
1 School of Chemistry, University of Reading Whiteknights, Reading, Berkshire RG6 6AD, UK 2 Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London 29-39 Brunswick Square, London WC1N 1AX, UK
*To whom correspondence should be addressed. Tel: +44 118 931 8215; Fax: +44 118 931 6331; Email: c.j.cardin{at}reading.ac.uk
Received September 7, 2006. Revised October 16, 2006. Accepted October 18, 2006.
Acridine-4-carboxamides form a class of known DNA mono-intercalating agents that exhibit cytotoxic activity against tumour cell lines due to their ability to inhibit topoisomerases. Previous studies of bis-acridine derivatives have yielded equivocal results regarding the minimum length of linker necessary between the two acridine chromophores to allow bis-intercalation of duplex DNA. We report here the 1.7 Å resolution X-ray crystal structure of a six-carbon-linked bis(acridine-4-carboxamide) ligand bound to d(CGTACG)2 molecules by non-covalent duplex cross-linking. The asymmetric unit consists of one DNA duplex containing an intercalated acridine-4-carboxamide chromophore at each of the two CG steps. The other half of each ligand is bound to another DNA molecule in a symmetry-related manner, with the alkyl linker threading through the minor grooves. The two crystallographically independent ligand molecules adopt distinct side chain interactions, forming hydrogen bonds to either O6 or N7 on the major groove face of guanine, in contrast to the semi-disordered state of mono-intercalators bound to the same DNA molecule. The complex described here provides the first structural evidence for the non-covalent cross-linking of DNA by a small molecule ligand and suggests a possible explanation for the inconsistent behaviour of six-carbon linked bis-acridines in previous assays of DNA bis-intercalation.
NDB code: DD0078 and PDB code: 2GB9