The Experts below are selected from a list of 15714 Experts worldwide ranked by ideXlab platform

Irving H Goldberg - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for the sequence specific DNA strand cleavage by the enediyne neocarzinostatin chromophore structure of the post activated chromophore DNA Complex
    Biochemistry, 1995
    Co-Authors: Xiaolian Gao, Adonis Stassinopoulos, Jeffrey S Rice, Irving H Goldberg
    Abstract:

    Neocarzinostatin chromophore (NCS chrom) belongs to a family of highly potent enediyne antitumor antibiotics which bind to specific DNA sequences and cause single- and/or double-strand lesions. NCS chrom-DNA Complexes have eluded structural studies since the native form of the Drug is extremely labile in aqueous conditions. We report the three-dimensional structure of the stable glutathione post-activated NCS chrom (NCSi-glu)-DNA Complex [NCSi-glu-d(GGAGCGC).d(GCGCTCC)] using NMR and distance geometry-molecular dynamics simulation methods. NCSi-glu interacts with the GCTC tetranucleotide on one strand and with the AGC trinucleotide on the other strand through the unique intercalation at the 5'-CT/5'-AG step and minor groove binding. The DNA-Drug Complex exhibits an extended, unwound V-shaped intercalation site and wider and shallower grooves than the free DNA duplex. The structure of the Complex manifests specific van der Waals interactions and H-bond formation between the carbohydrate moiety and a specific DNA sugar/phosphate. Prominent among those are the contacts of the NCSi-glu residues with the functional groups in the minor groove that are characteristic of individual DNA bases. These results provide a structural model for understanding the sequence specificity of the single- and double-strand cleavage at the AGC and related sites by the enediyne NCS chrom.

Xiaolian Gao - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for the sequence specific DNA strand cleavage by the enediyne neocarzinostatin chromophore structure of the post activated chromophore DNA Complex
    Biochemistry, 1995
    Co-Authors: Xiaolian Gao, Adonis Stassinopoulos, Jeffrey S Rice, Irving H Goldberg
    Abstract:

    Neocarzinostatin chromophore (NCS chrom) belongs to a family of highly potent enediyne antitumor antibiotics which bind to specific DNA sequences and cause single- and/or double-strand lesions. NCS chrom-DNA Complexes have eluded structural studies since the native form of the Drug is extremely labile in aqueous conditions. We report the three-dimensional structure of the stable glutathione post-activated NCS chrom (NCSi-glu)-DNA Complex [NCSi-glu-d(GGAGCGC).d(GCGCTCC)] using NMR and distance geometry-molecular dynamics simulation methods. NCSi-glu interacts with the GCTC tetranucleotide on one strand and with the AGC trinucleotide on the other strand through the unique intercalation at the 5'-CT/5'-AG step and minor groove binding. The DNA-Drug Complex exhibits an extended, unwound V-shaped intercalation site and wider and shallower grooves than the free DNA duplex. The structure of the Complex manifests specific van der Waals interactions and H-bond formation between the carbohydrate moiety and a specific DNA sugar/phosphate. Prominent among those are the contacts of the NCSi-glu residues with the functional groups in the minor groove that are characteristic of individual DNA bases. These results provide a structural model for understanding the sequence specificity of the single- and double-strand cleavage at the AGC and related sites by the enediyne NCS chrom.

Govindarajan Manikumar - One of the best experts on this subject based on the ideXlab platform.

  • human DNA topoisomerase i quantitative analysis of the effects of camptothecin analogs and the benzophenanthridine alkaloids nitidine and 6 ethoxydihydronitidine on DNA topoisomerase i induced DNA strand breakage
    Archives of Biochemistry and Biophysics, 1999
    Co-Authors: Joseph A Holden, Monroe E Wall, Mansukh C Wani, Govindarajan Manikumar
    Abstract:

    Human DNA topoisomerase I (topo I) has been purified from normal placenta and from a recombinant baculovirus expression system. A new radiolabeled plasmid DNA assay has been used to quantitate the activity of the purified enzymes and to compare the ability of several types of topo I-targeted Drugs to induce topo I-mediated DNA strand breaks. The 100-kDa recombinant enzyme form isolated from the baculovirus expression system is able to relax 2564 ng of supercoiled M-13 mp19 plasmid per minute per nanogram of enzyme. The addition of camptothecin (1 microM) to the reaction lowers the rate to 1282 ng per minute per nanogram of enzyme. The 100-kDa topo I from human placenta is able to relax 1092 ng of supercoiled plasmid per minute per nanogram of enzyme and the 68-kDa topo I form from placenta is able to relax 2069 ng of supercoiled plasmid per minute per nanogram of enzyme. Camptothecin (1 microM) decreases the relaxation rate of the placental enzymes about 50%. In the presence of several different types of topo I-targeted Drugs, both the recombinant and placental enzymes are induced to cleave plasmid DNA. Quantitative DNA cleavage assays with radioactive plasmid DNA and 9-aminocamptothecin, topotecan, SN-38, 10, 11-methylenedioxycamptothecin, 7-ethyl-10, 11-methylenedioxycamptothecin, 7-chloromethyl-10, 11-methylenedioxycamptothecin, nitidine, and 6-ethoxy-5, 6-dihydronitidine indicate that the order of potency in inducing topo I-mediated DNA breakage is methylenedioxycamptothecin analogs > SN-38 > 9-aminocamptothecin > topotecan and camptothecin > nitidine compounds. The order of potency correlates with the half-lives of the topo I-DNA Drug Complex determined with radiolabeled DNA in 0.45 M NaCl at 30 degrees C. The half-life of the Complex formed with 7-chloromethyl-10,11-methylenedioxycamptothecin is greater than 90 min whereas the half-life of the topo I-DNA Complex with 6-ethoxy-5, 6-dihydronitidine is less than 15 s. The other Drugs tested were found to have Drug Complex half-lives which fall between these two extremes.

Miriam Gochin - One of the best experts on this subject based on the ideXlab platform.

  • Nuclear Magnetic Resonance Characterization of a Paramagnetic DNA-Drug Complex with High Spin Cobalt; Assignment of the 1H and 31P NMR Spectra, and Determination of Electronic, Spectroscopic and Molecular Properties
    Journal of Biomolecular NMR, 1998
    Co-Authors: Miriam Gochin
    Abstract:

    The proton NMR spectrum of the ternary Complex between the octamer duplex d(TTGGCCAA)2, two molecules of the Drug chromomycin-A3, and a divalent cobalt ion has been assigned. Assignment procedures used standard two-dimensional techniques and relied upon the expected NOE contacts observed in the equivalent diamagnetic Complex containing zinc. The magnetic susceptibility tensor for the cobalt was determined and used to calculate shifts for all nuclei, aiding in the assignment process and verification. Relaxation, susceptibility, temperature and field dependence studies of the paramagnetic spectrum enabled determination of electronic properties of the octahedral cobalt Complex. The electronic relaxation rate τs was determined to be 2.5 ± 1.5 ps; the effective isotropic g value was found to be 2.6 ± 0.2, indicating strong spin-orbit coupling. The magnetic susceptibility tensor was determined to be χxx = 8.9 * 10-3 cm3/mol, χyy = 9.5 * 10-3 cm3/mol, χzz = 12.8 * 10-3 cm3/mol. A tentative rotational correlation time of 8 ns was obtained for the Complex. Both macroscopic and microscopic susceptibility measurements revealed deviations from Curie behavior over the temperature range accessible in the study. Non-selective relaxation rates were found to be inaccurate for defining distances from the metal center. However, pseudocontact shifts could be calculated with high accuracy using the dipolar shift equation. Isotropic hyperfine shifts were factored into contact and dipolar terms, revealing that the dipolar shift predominates and that contact shifts are relatively small.

Adonis Stassinopoulos - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for the sequence specific DNA strand cleavage by the enediyne neocarzinostatin chromophore structure of the post activated chromophore DNA Complex
    Biochemistry, 1995
    Co-Authors: Xiaolian Gao, Adonis Stassinopoulos, Jeffrey S Rice, Irving H Goldberg
    Abstract:

    Neocarzinostatin chromophore (NCS chrom) belongs to a family of highly potent enediyne antitumor antibiotics which bind to specific DNA sequences and cause single- and/or double-strand lesions. NCS chrom-DNA Complexes have eluded structural studies since the native form of the Drug is extremely labile in aqueous conditions. We report the three-dimensional structure of the stable glutathione post-activated NCS chrom (NCSi-glu)-DNA Complex [NCSi-glu-d(GGAGCGC).d(GCGCTCC)] using NMR and distance geometry-molecular dynamics simulation methods. NCSi-glu interacts with the GCTC tetranucleotide on one strand and with the AGC trinucleotide on the other strand through the unique intercalation at the 5'-CT/5'-AG step and minor groove binding. The DNA-Drug Complex exhibits an extended, unwound V-shaped intercalation site and wider and shallower grooves than the free DNA duplex. The structure of the Complex manifests specific van der Waals interactions and H-bond formation between the carbohydrate moiety and a specific DNA sugar/phosphate. Prominent among those are the contacts of the NCSi-glu residues with the functional groups in the minor groove that are characteristic of individual DNA bases. These results provide a structural model for understanding the sequence specificity of the single- and double-strand cleavage at the AGC and related sites by the enediyne NCS chrom.