title: Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Unit 1000, Houston, TX 77030, USA. maschuma@mdanderson.org
authors.forename: Maria A
authors.initials: MA
authors.lastname: Schumacher
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Piro
authors.forename: Weijun
authors.initials: W
authors.lastname: Xu
authors.forename: Sonja
authors.initials: S
authors.lastname: Hansen
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D004269:DNA, Bacterial / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004361:Drug Tolerance; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009875:Operator Regions, Genetic; D009876:Operon; D010444:Peptide Elongation Factor Tu / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D017510:Protein Folding; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D047428:Protein Kinase Inhibitors; C070740:hipB protein, E coli; C070741:hipA protein, E coli; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D010444:Peptide Elongation Factor Tu