1jo1: Difference between revisions
New page: left|200px<br /><applet load="1jo1" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jo1" /> '''N7-Guanine Adduct of 2,7-diaminomitosene wit... |
No edit summary |
||
| (13 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
== | ==N7-Guanine Adduct of 2,7-diaminomitosene with DNA== | ||
2,7-Diaminomitosene (2,7-DAM), the major metabolite of the antitumor | <StructureSection load='1jo1' size='340' side='right'caption='[[1jo1]]' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1jo1]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JO1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JO1 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAJ:DECARBAMOYL-2,7-DIAMINOMITOSENE'>DAJ</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1jo1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jo1 OCA], [https://pdbe.org/1jo1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1jo1 RCSB], [https://www.ebi.ac.uk/pdbsum/1jo1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1jo1 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:11523988</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 1jo1" style="background-color:#fffaf0;"></div> | ||
[[Category: Clement | == References == | ||
[[Category: Das | <references/> | ||
[[Category: Kumar | __TOC__ | ||
[[Category: Palom | </StructureSection> | ||
[[Category: Patel | [[Category: Large Structures]] | ||
[[Category: Paz | [[Category: Clement CC]] | ||
[[Category: Subramaniam | [[Category: Das A]] | ||
[[Category: Tomasz | [[Category: Kumar GS]] | ||
[[Category: Palom Y]] | |||
[[Category: Patel DJ]] | |||
[[Category: Paz MM]] | |||
[[Category: Subramaniam G]] | |||
[[Category: Tomasz M]] | |||
Latest revision as of 21:43, 29 November 2023
N7-Guanine Adduct of 2,7-diaminomitosene with DNAN7-Guanine Adduct of 2,7-diaminomitosene with DNA
Structural highlights
Publication Abstract from PubMed2,7-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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References |
| ||||||||||||||||||