Document Detail


Cooperative stabilization of Zn(2+):DNA complexes through netropsin binding in the minor groove of FdU-substituted DNA.
MedLine Citation:
PMID:  23153072     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The simultaneous binding of netropsin in the minor groove and Zn(2+) in the major groove of a DNA hairpin that includes 10 consecutive FdU nucleotides at the 3'-terminus (3'FdU) was demonstrated based upon NMR spectroscopy, circular dichroism (CD), and computational modeling studies. The resulting Zn(2+)/netropsin: 3'FdU complex had very high thermal stability with aspects of the complex intact at 85 °C, conditions that result in complete dissociation of Mg(2+) complexes. CD and (19)F NMR spectroscopy were consistent with Zn(2+) binding in the major groove of the DNA duplex and utilizing F5 and O4 of consecutive FdU nucleotides as ligands with FdU nucleotides hemi-deprotonated in the complex. Netropsin is bound in the minor groove of the DNA duplex based upon 2D NOESY data demonstrating contacts between AH2 (1)H and netropsin (1)H resonances. The Zn(2+)/netropsin: 3'FdU complex displayed increased cytotoxicity towards PC3 prostate cancer (PCa) cells relative to the constituent components or separate complexes (e.g. Zn(2+):3'FdU) indicating that this new structural motif may be therapeutically useful for PCa treatment. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:32.
Authors:
Supratim Ghosh; Freddie R Salsbury; David A Horita; William H Gmeiner
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-16
Journal Detail:
Title:  Journal of biomolecular structure & dynamics     Volume:  31     ISSN:  1538-0254     ISO Abbreviation:  J. Biomol. Struct. Dyn.     Publication Date:  2013  
Date Detail:
Created Date:  2013-10-09     Completed Date:  2014-04-09     Revised Date:  2014-11-04    
Medline Journal Info:
Nlm Unique ID:  8404176     Medline TA:  J Biomol Struct Dyn     Country:  England    
Other Details:
Languages:  eng     Pagination:  1301-10     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry*,  pharmacology
Binding Sites
Cations, Divalent
Circular Dichroism
Computer Simulation
Coordination Complexes / chemistry*,  pharmacology
Cytotoxins / metabolism
DNA / chemistry*
Floxuridine / chemistry*
Humans
Male
Netropsin / chemistry*
Nuclear Magnetic Resonance, Biomolecular
Nucleic Acid Conformation
Prostatic Neoplasms
Tumor Cells, Cultured
Zinc / chemistry*
Grant Support
ID/Acronym/Agency:
2P30CA12197-25/CA/NCI NIH HHS; CA102532/CA/NCI NIH HHS; CA12937/CA/NCI NIH HHS; P30 CA012197/CA/NCI NIH HHS; R01 CA129373/CA/NCI NIH HHS; U01 CA102532/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cations, Divalent; 0/Coordination Complexes; 0/Cytotoxins; 039LU44I5M/Floxuridine; 64B3O0RD7N/Netropsin; 9007-49-2/DNA; J41CSQ7QDS/Zinc
Comments/Corrections

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