1jo1: Difference between revisions
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'''N7-Guanine Adduct of 2,7-diaminomitosene with DNA''' | {{Structure | ||
|PDB= 1jo1 |SIZE=350|CAPTION= <scene name='initialview01'>1jo1</scene> | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=DAJ:DECARBAMOYL-2,7-DIAMINOMITOSENE'>DAJ</scene> | |||
|ACTIVITY= | |||
|GENE= | |||
}} | |||
'''N7-Guanine Adduct of 2,7-diaminomitosene with DNA''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1JO1 is a [ | 1JO1 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/ ]. 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:// | 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: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Clement, C C.]] | [[Category: Clement, C C.]] | ||
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[[Category: major groove binding drug]] | [[Category: major groove binding drug]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:06:01 2008'' | ||
Revision as of 13:06, 20 March 2008
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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
1JO1 is a Protein complex structure of sequences from [1]. 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
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