(dA.dT)-dependent inactivation of the DNA template properties by interaction with netropsin and distamycin A

Wähnert, U.; Zimmer, Ch.; Luck, G.; Pitra, C.

doi:10.1093/nar/2.3.391

Cited by 53 publications

(23 citation statements)

References 14 publications

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“…This large difference in thermodynamic behavior undoubtedly reflects a difference in conformation or in hydration between the homo-and heteropolymers, as does the observation (12,13,29,30) that netropsin binds less well to alternating poly(dA-dT) than to poly(dA).poly(dT). The nature of this difference is unknown, although Klug et al (31) have proposed that poly(dA-dT) has a noncanonical alternating B helix structure.…”

mentioning

confidence: 99%

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Kopka¹,

Yoon²,

Goodsell³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

800

577

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X-ray analysis of the complex of netropsin with the B-DNA dodecamer of sequence C-G-C-G-A-A-T-TBrC-G-C-G reveals that the antitumor antibiotic binds within the minor groove by displacing the water molecules of the spine of hydration. Netropsin amide NH furnish hydrogen bonds to bridge DNA adenine N-3 and thymine 0-2 atoms occurring on adjacent base pairs and opposite helix strands, exactly as with the spine of hydration. The narrowness of the groove forces the netropsin molecule to sit symmetrically in the center, with its two pyrrole rings slightly non-coplanar so that each ring is parallel to the walls of its respective region of the groove. Drug binding neither unwinds nor elongates the double helix, but it does force open the minor groove by 0.5-2.0 A, and it bends back the helix axis by 8°across the region of attachment. The netropsin molecule has an intrinsic twist that favors insertion into the minor groove of B-DNA, and it is given a small additional twist upon binding. The base specificity that makes netropsin bind preferentially to runs of four or more ACT base pairs is provided not by hydrogen bonding but by close van der Waals contacts between adenine C-2 hydrogens and CH groups on the pyrrole rings of the drug molecule. Substitution of one or more pyrroles by imidazole could permit recognition of G'C base pairs as well, and it could lead to a class of synthetic "lexitropsins," capable of reading any desired short sequence of DNA base pairs.Netropsin and its close relative distamycin ( Fig. 1) are antiviral antitumor antibiotics that, although too toxic for clinical use, have received extensive study as the paradigms of base-specific yet non-intercalative DNA-binding drug molecules. First isolated from Streptomyces netropsis in 1951 (1, 2), netropsin exerts its biological activity by binding tightly to double-helical B-DNA, interfering with both replication and transcription (3, 4). It shows little or no affinity for single-stranded DNA or RNA or for double-stranded RNA or DNA-RNA hybrids (3-5), suggesting that it does not bind to the A helix. It also fails to bind to left-handed Z-DNA; in fact, binding of netropsin to DNA favors A-to-B and Z-to-B helix transitions (6, 7).Chemical protection studies (3,4,8) and Overhauser NMR experiments (9) indicate that netropsin does not intercalate between base pairs, but it binds within the minor groove of the intact double helix, using hydrogen bonds between netropsin amide NH and exposed adenine N-3 and thymine 0-2 on the floor of the minor groove. The drug molecule attaches to clusters of four or more A'T or ITC, but not to G-C, base pairs (3, 10, 11). Alternating A-T-A-T regions bind netropsin less well than continuous runs of A or T (12, 13). Binding involves both an electrostatic component from the two cationic ends and hydrogen bonds from the central three amide NH groups, although neither aspect is absolute- FIG. 1. The netropsin molecule can be regarded as being assembled from (left to right): guanidinium, amide, methylpyrrole, amide, methylpyrr...

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mentioning

confidence: 99%

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Kopka¹,

Yoon²,

Goodsell³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

800

577

View full text Add to dashboard Cite

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“…Continuous runs of A or T appear to bind Nt more efficiently than do alternating ATAT tracts [6,7], resulting in a preference for binding to the DNA in the order AATT > TAAT = TTAA = ATAT > TATA [8].…”

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confidence: 99%

Netropsin interactions in the minor groove of d(GGCCAATTGG) studied by a combination of resolution enhancement and ab initio calculations

et al. 2005

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The structure of the complex between the minor groove binder netropsin and d(GGCCAATTGG) was determined via single‐crystal X‐ray techniques. The structure was refined to completion using refmac5.1.24, resulting in a residual R‐factor of 20.0% (including 68 water molecules). Using crystal engineering and cryocooling techniques, the resolution could be enhanced to 1.75 Å, resulting in an unambiguous determination of the drug conformation and orientation. As previously noticed, bifurcated hydrogen bonds are formed between the amide nitrogen atoms of the drug and the N3 and O2 atoms of A and T base pairs, respectively, clearly cataloging the structure to class I. As the bulky NH2 group on guanine was believed to prevent binding of the drug in the minor groove, the detailed nature of several of the amidinium and guanidinium end contacts were further investigated by ab initio quantum chemical methods.

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“…Accordingly, the oligopeptide antibiotics netropsin and distamycin A inhibit nucleic acid synthesis depending on the base composition of the template DNA. 14 Dickerson et al solved the crystal structure of netropsin bound to the nucleotide sequence d (CGCGAATTCGCG) and proposed that the substitution of imidazole (I) for pyrrole (P) in netropsin generates a class of small molecules that can read G/C-containing base sequences. 15 A DNA minor-groove-binding peptide that reads the sequence (5¤(A, T)GCGC(A, T)3¤) suggested the formation of a 2:1 positively cooperative complex with a four-ligand (IPPI).…”

Section: Development Of Innovative Dna-based Sequencespecific Small Mmentioning

confidence: 99%

Nature-Inspired Design of Smart Biomaterials Using the Chemical Biology of Nucleic Acids

Pandian¹,

Sugiyama²

2016

Bulletin of the Chemical Society of Japan

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In the natural cellular environment, nucleic acid biomolecules like DNA have biological implications via structural modifications and through precise coordination with other biomolecules in the local environment. Here, we detail the design of nature-inspired smart biomaterials that are based on the chemical biology of nucleic acids. N-Methylpyrrole (P) and N-methylimidazole (I) polyamides (PIPs), sequence-specific DNA-binding molecules have been, developed to image specific DNA sequences and to alter gene expression inside the living cells. The self-assembling feature of DNA was harnessed to achieve the programmed assembly of nanostructures with different dimensions. Also, the advanced DNA architectures with well-defined properties allowed the real-time visualization of the complicated single-molecule interactions, which in-turn provided vital intracellular mechanistic information. The molecular recognition properties of DNA were exploited to design biologically inspired hybrid catalysts for sustainable organic synthesis. Our review could serve as a guidebook for researchers who aim to develop nucleic acid-based synthetic biomaterials.

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(dA.dT)-dependent inactivation of the DNA template properties by interaction with netropsin and distamycin A

Cited by 53 publications

References 14 publications

The molecular origin of DNA-drug specificity in netropsin and distamycin.

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Netropsin interactions in the minor groove of d(GGCCAATTGG) studied by a combination of resolution enhancement and ab initio calculations

Nature-Inspired Design of Smart Biomaterials Using the Chemical Biology of Nucleic Acids

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