Title: Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB. | Journal: Science (New York, N.Y.). 2009 Jan;323(5912):396-401 | Authors: Schumacher MA, Piro KM, Xu W, Hansen S, Lewis K, Brennan RG. | 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, approximately 70 degrees 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. | See full PubMed entry: http://www.ncbi.nlm.nih.gov/pubmed/19150849 |
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