Phosphoaminoglycosides Inhibit SWI2/SNF2 Family DNA-Dependent Molecular Motor Domains

• Published in: Biochemistry (Easton) 2000-04, Vol.39 (15), p.4358-4365
• Main Authors: Muthuswami, Rohini, Mesner, Larry D, Wang, Dongyan, Hill, David A, Imbalzano, Anthony N, Hockensmith, Joel W
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Adenosine Triphosphate - metabolism; Animals; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Catalytic Domain - drug effects; Cattle; DNA - genetics; DNA - metabolism; DNA Helicases - antagonists & inhibitors; DNA Helicases - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - growth & development; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - metabolism; Humans; Kanamycin - analogs & derivatives; Kanamycin - metabolism; Kanamycin - pharmacology; Molecular Motor Proteins - antagonists & inhibitors; Molecular Motor Proteins - chemistry; Molecular Motor Proteins - genetics; Molecular Motor Proteins - metabolism; Multigene Family; Neomycin - analogs & derivatives; Neomycin - metabolism; Neomycin - pharmacology; Nuclear Proteins; Nucleosomes - drug effects; Nucleosomes - metabolism; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; phosphoaminoglycosides; Phosphorylation; Saccharomyces cerevisiae Proteins; SNF2 protein; Substrate Specificity; SWI2 protein; TATA-Binding Protein Associated Factors; TATA-Box Binding Protein; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi992503r

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.