1fj5
From Proteopedia
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TAMOXIFEN-DNA ADDUCT
Overview
The non-steroidal anti-estrogen tamoxifen [TAM] has been in clinical use, over the last two decades as a potent adjunct chemotherapeutic agent for, treatment of breast cancer. It has also been given prophylactically to, women with a strong family history of breast cancer. However, tamoxifen, treatment has also been associated with increased endometrial cancer, possibly resulting from the reaction of metabolically activated tamoxifen, derivatives with cellular DNA. Such DNA adducts can be mutagenic and the, activities of isomeric adducts may be conformation-dependent. We therefore, investigated the high resolution NMR solution conformation of one covalent, adduct (cis-isomer, S-epimer of [TAM]G) formed from the reaction of, tamoxifen [TAM] to N(2)-of guanine in the d(C-[TAM]G-C).d(G-C-G) sequence, context at the 11-mer oligonucleotide duplex level. Our NMR results, establish that the S-cis [TAM]G lesion is accomodated within a widened, minor groove without disruption of the Watson-Crick [TAM]G. C and flanking, Watson-Crick G.C base-pairs. The helix axis of the bound DNA oligomer is, bent by about 30 degrees and is directed away from the minor groove adduct, site. The presence of such a bulky [TAM]G adduct with components of the, TAM residue on both the 5'- and the 3'-side of the modified base could, compromise the fidelity of the minor groove polymerase scanning machinery.
About this Structure
1FJ5 is a Protein complex structure of sequences from [1] with TAX as ligand. Full crystallographic information is available from OCA.
Reference
Accomodation of S-cis-tamoxifen-N(2)-guanine adduct within a bent and widened DNA minor groove., Shimotakahara S, Gorin A, Kolbanovskiy A, Kettani A, Hingerty BE, Amin S, Broyde S, Geacintov N, Patel DJ, J Mol Biol. 2000 Sep 15;302(2):377-93. PMID:10970740
Page seeded by OCA on Sat Nov 24 23:54:04 2007
