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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Crystallization
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Crystallography, X-Ray
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DNA, Bacterial / chemistry
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DNA, Bacterial / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dimerization
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Drug Tolerance*
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Escherichia coli / chemistry
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Escherichia coli / drug effects*
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Escherichia coli / genetics
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Escherichia coli / metabolism*
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Escherichia coli Proteins / antagonists & inhibitors
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Escherichia coli Proteins / chemistry
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Escherichia coli Proteins / genetics
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Escherichia coli Proteins / metabolism*
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Models, Molecular
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Nucleic Acid Conformation
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Operator Regions, Genetic
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Operon
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Peptide Elongation Factor Tu / metabolism
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Phosphorylation
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Protein Conformation
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Protein Folding
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Protein Kinase Inhibitors / metabolism
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Protein Kinases / chemistry
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Protein Kinases / metabolism
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Protein Structure, Secondary
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Protein Structure, Tertiary
Substances
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DNA, Bacterial
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DNA-Binding Proteins
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Escherichia coli Proteins
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Protein Kinase Inhibitors
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hipB protein, E coli
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hipA protein, E coli
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Adenosine Triphosphate
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Protein Kinases
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Peptide Elongation Factor Tu
Associated data
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PDB/3DNT
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PDB/3DNU
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PDB/3DNV
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PDB/3DNW