Induced Formation of a DNA Bulge Structure by a Molecular Wedge Ligand−Postactivated Neocarzinostatin Chromophore

Gao, Xiaolian; Stassinopoulos, Adonis; Ji, Jie; Kwon, Young Joo; Bare, Simona; Goldberg, Irving H.

doi:10.1021/bi012112o

Cited by 25 publications

(52 citation statements)

References 17 publications

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“…As a result, the more flexible dA5·dT14 pair of the NCSigb•bulged DNA complex is much more twisted and buckled than that of the dG20·dC8 pair in the SCA-α2•bulged DNA complex ( Figure 6A and C). The G20 residue stacks right above the BI ring platform and results in the NMR up-field shift of the G20 imino proton due to ring current effect ( Figure 6A and C); on the other hand, the T14 residue stacks poorly, off-center and tilted, on the THI ring platform (Figure 6B and D) and, therefore, exhibits much less upfield shift than expected (16). Accordingly, it was proposed that the removal of the bulky cyclocarbonate moiety would likely improve the binding behavior (16,17).…”

Section: Structural Comparison Of the Two Complexesmentioning

confidence: 82%

“…The imino, amino and nonexchangeable protons have been assigned using standard methodologies described in previous publications (16,21,27). Imino-imino NOE connectivities are observed between all adjacent base-pairs on either side of the bulge (peaks a to g in Figure 3A).…”

Section: Noe Analysis Of Imino Proton Regionmentioning

confidence: 99%

“…1D, one-dimensional 2D, two-dimensional BI, benzindanol DQF-COSY, double-quantum-filtered correlation spectroscopy NCS, neocarzinostatin NCS-chrom, native form of the NCS chromophore NCSi-gb, postactivated NCS-chrom formed under base-catalyzed conditions NMF, 2-N-methylfucosamine NMR, nuclear magnetic resonance NA, dihydronaphthone NOE, nuclear Overhauser effect NOESY, nuclear Overhauser effect and exchange spectroscopy rmsd, root-mean-square deviation SCA, spirocyclic alkene THI, tetrahydroindacene TOCSY, total correlation spectroscopy Chemical structures of (A) natural metabolite NCSi-gb, (B) sequence of its 18-mer bulged DNA substrate with an artificial chemical-linker loop (15,16), (C) synthetic analogue SCA-α2, and (D) sequence of its 25-mer bulged DNA substrate. The aromatic ring moieties of both ligands are marked.…”

Section: Abbreviationsmentioning

confidence: 99%

“…The solution structures of the complexes formed between oligodeoxynucleotides containing a two-base bulge and the natural, as well as analogue ligands in which the aminosugar is β-linked to the spirocyclic ring (17), have been elucidated using high-resolution NMR spectroscopy and restrained molecular dynamic simulation (15,16,21,22). The structures of the complexes reveal, in important details, the differences in binding modes, which provide insight into the relationship between structure and binding affinity.…”

Section: Introductionmentioning

confidence: 99%

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Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA

et al. 2007

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The solution structure of the complex formed between an oligodeoxynucleotide containing a twobase bulge (5′-CCATCGTCTACCTTTGGTAGGATGG) and SCA-α2, a designed spirocyclic helical molecule, has been elucidated. SCA-α2, a close mimic of the metabolite, NCSi-gb, of the DNA bulge-specific enediyne antibiotic neocarzinostatin, differs in possessing a more stable spirocyclic ring system and in lacking certain bulky groupings that compromise bulged DNA binding. This study provides a detailed comparison of the binding modes of the two complexes and provides new insights into the importance of shape and space, as opposed to simple nucleotide sequence, in complex formation at the bulge site. The two rigidly held aromatic rings of SCA-α2 form a righthanded helical molecular wedge that specifically penetrates the bulge binding pocket and immobilizes the two bulge residues (GT), which point towards the minor groove, rather than the major groove as in the NCSi-gb•bulged DNA complex. The ligand aromatic ring systems stack on the DNA bulge-flanking base pairs that define the long sides of the triangular prism binding pocket. Like NCSi-gb, SCA-α2 possesses the natural N-methyl furanose moiety, α-linked to the benzindanol (BI) moiety. The aminosugar anchors in the major groove of the DNA and points toward the 3′-bulgeflanking base pair. Lacking the bulky cyclocarbonate of NCSi-gb, the SCA-α2•bulged DNA complex has a much less twisted and buckled 3'-bulge-flanking base pair (dG20·dC8), and the G20 residue stacks directly above the BI ring platform. Also, the absence of the methyl group and the free rotation of the methoxy group on the dihydronaphthanone (NA) moiety of SCA-α2 allow better stacking geometry of the NA ring above the 5′-bulge-flanking base pair dG21·dC5. These and other considerations help to explain why NCSi-gb binds very poorly to bulged RNA and are consistent with the recent observation of good binding with SCA-α2. Thus, although the two complexes resemble each other closely, they differ in important local environmental details. SCA-α2 has a better * To whom correspondence should be addressed: Irving H. Goldberg, Telephone: (617) (Table S1), proton chemical shift changes (ppm) of the bound form of SCA-α2 in the SCA-α2•bulged 25-mer DNA complex (in D 2 O at 25 °C) relative to the free form of SCA-α2 (in d4-MeOH at 25 °C) (Table S2), the exchangeable proton chemical shifts (ppm) of DNA components within the SCA-α2•bulged 25-mer DNA complex in H 2 O buffer at pH 6.8 and 10°C (Table S3 A), the non-exchangeable proton chemical shifts (ppm) of DNA components within the SCA-α2•bulged 25-mer DNA complex in D 2 O buffer at pH 6.8 and 10°C (Table S3 B), the titration of various amount of SCA-α2 into 25-mer bulged DNA as monitored by 1 H NMR spectra shown as expanded imino proton region ( Figure S1), the expanded NOESY (200 ms mixing time) contour plots of the SCA-α2•bulged 25mer DNA complex, focusing on the amino and aromatic proton regions ( Figure S2), the expanded NOESY (200 ms mixing time) contour plots for the b...

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Section: Structural Comparison Of the Two Complexesmentioning

confidence: 82%

Section: Noe Analysis Of Imino Proton Regionmentioning

confidence: 99%

Section: Abbreviationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA

et al. 2007

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“…In these cases, the conformation and surface properties of nucleic acids likely contribute to the observed rate enhancements of reaction (18)(19)(20)(21)(22)(23)(24)(25). Probably the best studied example of this type of DNA-promoted process involves nucleobase reaction with cyclopropylpyrroloindole derivatives such as those found in natural products CC-1065 and the duocarmycins as well as a related synthetic analog bizelsin, currently undergoing clinical investigation (26)(27)(28)(29).…”

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confidence: 99%