Secondary structure specificity of the nuclease activity of the 1,10-phenanthroline-copper complex.

Pope, L. S.; Sigman, David S.

doi:10.1073/pnas.81.1.3

Cited by 110 publications

(30 citation statements)

References 38 publications

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“…Next, we attempted to confirm the binding site of SMN-C2 using an RNA footprinting experiment in the context of a longer RNA sequence containing the entire exon 7. Iron or copper chelates in the presence of hydrogen peroxide have previously been used as an artificial chemical ribonuclease to probe the nucleic acid binding sites of molecules (25). Conjugation of the metal ion chelate to a nucleic acid binding molecule leads to oxidative cleavage of the phosphate sugar backbone adjacent to the binding site (26).…”

Section: Significancementioning

confidence: 99%

Mechanistic studies of a small-molecule modulator of SMN2 splicing

Wang

Schultz

Johnson

2018

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

115

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RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA-binding ligands that modulate pre-mRNA splicing. Chemical proteomic and genomic techniques reveal that SMN-C2 directly binds to the AGGAAG motif on exon 7 of the SMN2 pre-mRNA, and promotes a conformational change in two to three unpaired nucleotides at the junction of intron 6 and exon 7 in both in vitro and in-cell models. This change creates a new functional binding surface that increases binding of the splicing modulators, far upstream element binding protein 1 (FUBP1) and its homolog, KH-type splicing regulatory protein (KHSRP), to the SMN-C2/C3-SMN2 pre-mRNA complex and enhances SMN2 splicing. These findings underscore the potential of small-molecule drugs to selectively bind RNA and modulate pre-mRNA splicing as an approach to the treatment of human disease.

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Section: Significancementioning

confidence: 99%

Mechanistic studies of a small-molecule modulator of SMN2 splicing

Wang

Schultz

Johnson

2018

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

115

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“…Actually, Hathaway and his collaborators have reported that structural distortions in [Cu(phen) 2 X ][ Y ] complexes ( X = Cl − , Br − , Y = various negative ions) depend upon X and Y , indicating that the copper coordination spheres are flexible and change with the environment [ 50 , 51 ]. It has been suggested that the cuprous complex [Cu(phen) 2 ] + cleaves B-form DNA much faster than it does A-form DNA because the complex has stronger affinity to the minor groove of B-form DNA than that of A-form DNA [ 52 , 53 , 54 , 55 , 56 ]. In addition, the difference in the coordination structures of [Cu(phen) 2 (H 2 O)] 2+ bound to A- and B-forms of DNA might be another factor responsible for the difference in the rate of cleavage.…”

Section: Interaction Of Cu(ii) Complexes Of Phen and Its Derivativmentioning

confidence: 99%

Interaction of DNA with Simple and Mixed Ligand Copper(II) Complexes of 1,10-Phenanthrolines as Studied by DNA-Fiber EPR Spectroscopy

Chikira

Palaniandavar

2015

IJMS

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The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related to the DNA binding modes of the complexes such as intercalation, groove binding, and electrostatic surface binding. A variety of spectroscopic methods have been used to study the DNA binding mode of the Cu(II) complexes. Of all these methods, DNA-fiber electron paramagnetic resonance (EPR) spectroscopy affords unique information on the DNA binding structures of the complexes. In this review we summarize the results of our DNA-fiber EPR studies on the DNA binding structure of the complexes and discuss them together with the data accumulated by using other measurements.

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“…Using these structural and functional data as a starting (Moser and Dervan 1987;Hall and Fox 1999), whereas Cu(II):1,10-orthophenanthroline (Cu:oP) interacts preferentially with bulged or stacked single-stranded regions of rRNA and generates more localized (Pope and Sigman 1984;Johnson and Nazhat 1987;Mazumder et al 1992), and generally lessrobust RNA cleavages compared with Fe-EDTA (Bowen et al 2001).…”

Section: Experimental Strategymentioning

confidence: 99%

Ribosomal localization of translation initiation factor IF2

Marzi¹,

Knight²,

Brandi³

et al. 2003

RNA

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Bacterial translation initiation factor IF2 is a GTP-binding protein that catalyzes binding of initiator fMet-tRNA in the ribosomal P site. The topographical localization of IF2 on the ribosomal subunits, a prerequisite for understanding the mechanism of initiation complex formation, has remained elusive. Here, we present a model for the positioning of IF2 in the 70S initiation complex as determined by cleavage of rRNA by the chemical nucleases Cu(II):1,10-orthophenanthroline and Fe(II):EDTA tethered to cysteine residues introduced into IF2. Two specific amino acids in the GII domain of IF2 are in proximity to helices H3, H4, H17, and H18 of 16S rRNA. Furthermore, the junction of the C-1 and C-2 domains is in proximity to H89 and the thiostrepton region of 23S rRNA. The docking is further constrained by the requisite proximity of the C-2 domain with P-site-bound tRNA and by the conserved GI domain of the IF2 with the large subunit's factor-binding center. Comparison of our present findings with previous data further suggests that the IF2 orientation on the 30S subunit changes during the transition from the 30S to 70S initiation complex.

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Secondary structure specificity of the nuclease activity of the 1,10-phenanthroline-copper complex.

Abstract: The artificial DNase activity of the 1,10-

Cited by 110 publications

References 38 publications

Mechanistic studies of a small-molecule modulator of SMN2 splicing

Mechanistic studies of a small-molecule modulator of SMN2 splicing

Interaction of DNA with Simple and Mixed Ligand Copper(II) Complexes of 1,10-Phenanthrolines as Studied by DNA-Fiber EPR Spectroscopy

Ribosomal localization of translation initiation factor IF2

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