High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA

Eis, Peggy S.; Smith, Jarrod A.; Rydzewski, Jan M.; Case, David A.; Boger, Dale L.; Chazin, Walter J.

doi:10.1006/jmbi.1997.1223

Cited by 48 publications

(59 citation statements)

References 53 publications

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“…The biological activity of these natural products is related to a characteristic sequence-selective alkylation of adenine N3 in AT-rich sites by the least substituted carbon of the activated cyclopropane ( Fig. 2) [5,6]. This minor groove binding is thought to initiate a cascade of cellular events leading to apoptosis as observed for the duocarmycins [7].…”

Section: Investigations Of Cc-1065 the Duocarmycins And Synthetic Anmentioning

confidence: 98%

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

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CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products

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Section: Investigations Of Cc-1065 the Duocarmycins And Synthetic Anmentioning

confidence: 98%

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

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“…In particular, an approach based on integrated NMR experimental data with GIAO 1 H NMR DFT calculated values was proposed to study ligand-macromolecule interactions, going well over the successful application of 1 H and 13 C NMR chemical shift calculations in the structure elucidation of organic molecules, [8a,9b,28] in the interpretation of polymer spectra [28d] and in the conformational analysis of peptides, [91][92][93] oligosaccharides, [94] and calixarenes. [95] Thus, two 3D models were built where 36 was covalently bound to A5 or A6 (model A or B, respectively; Figure 11a,b), and starting from the NMR structure of duocarmycin SA covalently linked to the DNA duplex (PDB [96] archive code 1DSA) [97] 36 was built and docked in the minor groove. [24] In order to perform quantum mechanical calculations in a reasonable computation time and with a reliable model, only six base pairs of the DNA were considered (Figure 11).…”

Section: Quantum Mechanical Calculation Of Nmr Parameters As a Tool Fmentioning

confidence: 99%

Quantum Mechanical Calculation of NMR Parameters in the Stereostructural Determination of Natural Products

et al. 2010

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The present microreview highlights the recent goals reached by the application of a combined approach of NMR spectroscopy and quantum chemical methods in the structural studies of natural products. In particular, different case studies are reported, showing the comparison of calculated NMR parameters at the quantum mechanical (QM) theory level with experimental data for the configurational assignment of organic compounds. Moreover, it is shown that the QM-NMR

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“…32,33 The starting ensemble of 40 structures, which differ considerably in helical geometry (RMSD 3.46 Å ), were generated using the Nucleic Acids Builder program NAB †. These structures were positioned with the polyamide and docked using a restrained molecular dynamics (rMD) simulated annealing (SA) protocol in the AMBER 6.0 software package.…”

Section: Structure Calculationsmentioning

confidence: 99%

“…5.0, þ 1.9 Å . 32 The constraints were supplemented with additional distance constraints from labile protons identified in the 100 ms NOESY spectrum in protiated solvent. All distance constraints assigned from NOEs were given a lower bound of 1.8 Å as the sum of van der Waals radii.…”

Section: Distance Constraintsmentioning

confidence: 99%

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Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

Urbach

Love

Ross

et al. 2002

Journal of Molecular Biology

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Polyamides composed of N-methylpyrrole (Py), N-methylimidazole (Im) and N-methylhydroxypyrrole (Hp) amino acids linked by b-alanine (b) bind the minor groove of DNA in 1:1 and 2:1 ligand to DNA stoichiometries. Although the energetics and structure of the 2:1 complex has been explored extensively, there is remarkably less understood about 1:1 recognition beyond the initial studies on netropsin and distamycin. We present here the 1:1 solution structure of ImPy -b -Im-b -ImPy -b-Dp bound in a single orientation to its match site within the DNA duplex 5 0 -CCAAAGAGAAGCG-3 0 ·5 0 -CGCTTCTCTTTGG-3 0 (match site in bold), as determined by 2D 1 H NMR methods. The representative ensemble of 12 conformers has no distance constraint violations greater than 0.13 Å and a pairwise RMSD over the binding site of 0.80 Å . Intermolecular NOEs place the polyamide deep inside the minor groove, and oriented N -C with the 3 0 -5 0 direction of the purine-rich strand. Analysis of the high-resolution structure reveals the ligand bound 1:1 completely within the minor groove for a full turn of the DNA helix. The DNA is B-form (average rise ¼ 3.3 Å , twist ¼ 388) with a narrow minor groove closing down to 3.0-4.5 Å in the binding site. The ligand and DNA are aligned in register, with each polyamide NH group forming bifurcated hydrogen bonds of similar length to purine N3 and pyrimidine O2 atoms on the floor of the minor groove. Each imidazole group is hydrogen bonded via its N3 atom to its proximal guanine's exocyclic amino group. The important roles of b-alanine and imidazole for 1:1 binding are discussed.

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High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA

Cited by 48 publications

References 53 publications

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Quantum Mechanical Calculation of NMR Parameters in the Stereostructural Determination of Natural Products

Structure of a β-Alanine-linked Polyamide Bound to a Full Helical Turn of Purine Tract DNA in the 1:1 Motif

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