1. Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipB.
- Author
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Schumacker, Maria A., Piro, Kevin M., Xu, Weijun, Hansen, Sonja, Lewis, Kim, and Brennan, Richard G.
- Subjects
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DRUG tolerance , *NEUTRALIZATION (Chemistry) , *BACTERIA , *BACTERIAL genetics , *ESCHERICHIA coli , *SERINE , *EUKARYOTIC cells , *GENETIC translation , *PHYSIOLOGY - Abstract
Bacterial multidrug tolerance is largely responsible for the inability of antibiotics to eradicate infections and is caused by a small population of dormant bacteria called persisters. HipA is a critical Escherichia coli persistence factor that is normally neutralized by HipB, a transcription repressor, which also regulates hipBA expression. Here, we report multiple structures of HipA and a HipA-HipB-DNA complex. HipA has a eukaryotic serine/threonine kinase--like fold and can phosphorylate the translation factor EF-Tu, suggesting a persistence mechanism via cell stasis. The HipA-HipB-DNA structure reveals the HipB-operator binding mechanism, ~70° DNA bending, and unexpected HipA-DNA contacts. Dimeric HipB interacts with two HipA molecules to inhibit its kinase activity through sequestration and conformational inactivation. Combined, these studies suggest mechanisms for HipA-mediated persistence and its neutralization by HipB. [ABSTRACT FROM AUTHOR]
- Published
- 2009