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'''N7-Guanine Adduct of 2,7-diaminomitosene with DNA''' | '''N7-Guanine Adduct of 2,7-diaminomitosene with DNA''' | ||
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==About this Structure== | ==About this Structure== | ||
Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JO1 OCA]. | |||
==Reference== | ==Reference== | ||
Solution structure of a guanine-N7-linked complex of the mitomycin C metabolite 2,7-diaminomitosene and DNA. Basis of sequence selectivity., Subramaniam G, Paz MM, Suresh Kumar G, Das A, Palom Y, Clement CC, Patel DJ, Tomasz M, Biochemistry. 2001 Sep 4;40(35):10473-84. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11523988 11523988] | Solution structure of a guanine-N7-linked complex of the mitomycin C metabolite 2,7-diaminomitosene and DNA. Basis of sequence selectivity., Subramaniam G, Paz MM, Suresh Kumar G, Das A, Palom Y, Clement CC, Patel DJ, Tomasz M, Biochemistry. 2001 Sep 4;40(35):10473-84. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11523988 11523988] | ||
[[Category: Clement, C C.]] | [[Category: Clement, C C.]] | ||
[[Category: Das, A.]] | [[Category: Das, A.]] | ||
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[[Category: Subramaniam, G.]] | [[Category: Subramaniam, G.]] | ||
[[Category: Tomasz, M.]] | [[Category: Tomasz, M.]] | ||
[[Category: | [[Category: Double helix]] | ||
[[Category: | [[Category: Guanine-n7-alkylator]] | ||
[[Category: | [[Category: Major groove binding drug]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 21:29:10 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 21:29, 2 May 2008
N7-Guanine Adduct of 2,7-diaminomitosene with DNA
OverviewOverview
2,7-Diaminomitosene (2,7-DAM), the major metabolite of the antitumor antibiotic mitomycin C, forms DNA adducts in tumor cells. 2,7-DAM was reacted with the deoxyoligonucleotide d(GTGGTATACCAC) under reductive alkylation conditions. The resulting DNA adduct was characterized as d(G-T-G-[M]G-T-A-T-A-C-C-A-C) (5), where [M]G stands for a covalently modified guanine, linked at its N7-position to C10 of the mitosene. The adducted oligonucleotide complements with itself, retaining 2-fold symmetry in the 2:1 drug-duplex complex, and provides well-resolved NMR spectra, amenable for structure determination. Adduction at the N7-position of G4 ([M]G, 4) is characterized by a downfield shift of the G4(H8) proton and separate resonances for G4(NH(2)) protons. We assigned the exchangeable and nonexchangeable proton resonances of the mitosene and the deoxyoligonucleotide in adduct duplex 5 and identified intermolecular proton-proton NOEs necessary for structural characterization. Molecular dynamics computations guided by 126 intramolecular and 48 intermolecular distance restraints were performed to define the solution structure of the 2,7-DAM-DNA complex 5. A total of 12 structures were computed which exhibited pairwise rmsd values in the 0.54-1.42 A range. The 2,7-DAM molecule is anchored in the major groove of DNA by its C10 covalently linked to G4(N7) and is oriented 3' to the adducted guanine. The presence of 2,7-DAM in the major groove does not alter the overall B-DNA helical structure. Alignment in the major groove is a novel feature of the complexation of 2,7-DAM with DNA; other known major groove alkylators such as aflatoxin, possessing aromatic structural elements, form intercalated complexes. Thermal stability properties of the 2,7-DAM-DNA complex 5 were characteristic of nonintercalating guanine-N7 alkylating agents. Marked sequence selectivity of the alkylation by 2,7-DAM was observed, using a series of oligonucleotides incorporating variations of the 5'-TGGN sequence as substrates. The selectivity correlated with the sequence specificity of the negative molecular electrostatic potential of the major groove, suggesting that the alkylation selectivity of 2,7-DAM is determined by sequence-specific variation of the reactivity of the DNA. The unusual, major groove-aligned structure of the adduct 5 may account for the low cytotoxicity of 2,7-DAM.
About this StructureAbout this Structure
Full crystallographic information is available from OCA.
ReferenceReference
Solution structure of a guanine-N7-linked complex of the mitomycin C metabolite 2,7-diaminomitosene and DNA. Basis of sequence selectivity., Subramaniam G, Paz MM, Suresh Kumar G, Das A, Palom Y, Clement CC, Patel DJ, Tomasz M, Biochemistry. 2001 Sep 4;40(35):10473-84. PMID:11523988 Page seeded by OCA on Fri May 2 21:29:10 2008