Muthuswami R, Mesner L D, Wang D, Hill D A, Imbalzano A N, Hockensmith J W
Department of Biochemistry and Molecular Genetics 440, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Biochemistry. 2000 Apr 18;39(15):4358-65. 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.
SWI2/SNF2蛋白家族成员参与一系列核酸代谢功能，包括染色质重塑和转录。目前的研究确定了一种新策略，可特异性抑制SWI2/SNF2家族成员共有的功能性DNA依赖性腺苷三磷酸酶（ATP酶）运动结构域。我们已确定磷酸氨基糖苷类制剂，它们是耐氨基糖苷类细菌的天然产物，可作为三种SWI2/SNF2家族成员体外活性的抑制剂。这些化合物通过与DNA竞争来抑制活性DNA依赖性ATP酶A结构域（ADAAD）的ATP酶活性，因此对非DNA依赖性ATP酶或RNA依赖性ATP酶没有影响。在DNA依赖性ATP酶超家族中，这些化合物对SWI2/SNF2家族成员的作用最强，对其他DNA依赖性ATP酶的作用较弱。我们证明，靶向特定类型的DNA依赖性ATP酶而不影响其他ATP酶的功能是可行的。由于SWI2/SNF2蛋白被认为在DNA代谢的各个方面都发挥作用，本文为DNA代谢抑制剂的开发提供了一个原型。
