1fj5
From Proteopedia
(New page: 200px<br /><applet load="1fj5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fj5" /> '''TAMOXIFEN-DNA ADDUCT'''<br /> ==Overview== ...) |
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| - | [[Image:1fj5.gif|left|200px]]<br /><applet load="1fj5" size=" | + | [[Image:1fj5.gif|left|200px]]<br /><applet load="1fj5" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1fj5" /> | caption="1fj5" /> | ||
'''TAMOXIFEN-DNA ADDUCT'''<br /> | '''TAMOXIFEN-DNA ADDUCT'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The non-steroidal anti-estrogen tamoxifen [TAM] has been in clinical use | + | 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== | ==About this Structure== | ||
| - | 1FJ5 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with TAX as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1FJ5 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=TAX:'>TAX</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FJ5 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Geacintov, N.]] | [[Category: Geacintov, N.]] | ||
[[Category: Gorin, A.]] | [[Category: Gorin, A.]] | ||
| - | [[Category: Hingerty, B | + | [[Category: Hingerty, B E.]] |
[[Category: Kettani, A.]] | [[Category: Kettani, A.]] | ||
[[Category: Kolbanovskiy, A.]] | [[Category: Kolbanovskiy, A.]] | ||
| - | [[Category: Patel, D | + | [[Category: Patel, D J.]] |
[[Category: Shimotakahara, S.]] | [[Category: Shimotakahara, S.]] | ||
[[Category: TAX]] | [[Category: TAX]] | ||
[[Category: covalent dna-tamoxifen complex; groove binding; localized helical perturbation; widened minor groove]] | [[Category: covalent dna-tamoxifen complex; groove binding; localized helical perturbation; widened minor groove]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:39:13 2008'' |
Revision as of 10:39, 21 February 2008
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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 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
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