Phosphoaminoglycosides inhibit SWI2/SNF2 family DNA-dependent molecular motor domains.
Members of the SWI2/SNF2 family of proteins participate in an array of nucleic acid metabolic functions, including chromatin remodeling and transcription. The present studies identify a novel strategy to specifically inhibit the functional DNA-dependent adenosinetriphosphatase (ATPase) motor domain common to SWI2/SNF2 family members. We have identified preparations of phosphoaminoglycosides, which are natural products of aminoglycoside-resistant bacteria, as inhibitors of the in vitro activities of three SWI2/SNF2 family members. These compounds inhibit the ATPase activity of the active DNA-dependent ATPase A domain (ADAAD) by competing with respect to DNA and thus have no effect on DNA-independent ATPases or on RNA-dependent ATPases. Within the superfamily of DNA-dependent ATPases, these compounds are most potent toward SWI2/SNF2 family members and less potent toward other DNA-dependent ATPases. We demonstrate that it is feasible to target DNA-dependent ATPases of a particular type without affecting the function of other ATPases. As the SWI2/SNF2 proteins have been proposed to function in all aspects of DNA metabolism, this paper provides an archetype for development of DNA metabolic inhibitors.
Muthuswami
R
R
Department of Biochemistry and Molecular Genetics 440, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Mesner
L D
LD
Wang
D
D
Hill
D A
DA
Imbalzano
A N
AN
Hockensmith
J W
JW
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D002417:Cattle; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007612:Kanamycin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D020409:Molecular Motor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D009355:Neomycin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D009687:Nuclear Proteins; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D029701:Saccharomyces cerevisiae Proteins; D013379:Substrate Specificity; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D020409:Molecular Motor Proteins; D009687:Nuclear Proteins; D009707:Nucleosomes; D010446:Peptide Fragments; C499336:SMARCA1 protein, human; C084011:SMARCA2 protein, human; C499338:SNF2L protein, Bos taurus; D029701:Saccharomyces cerevisiae Proteins; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; D007612:Kanamycin; D000255:Adenosine Triphosphate; D004247:DNA; D000251:Adenosine Triphosphatases; C073676:MOT1 protein, S cerevisiae; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D009355:Neomycin