title: Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system.
abstract: TipA is a transcriptional regulator found in diverse bacteria. It constitutes a minimal autoregulated multidrug resistance system against numerous thiopeptide antibiotics. Here we report the structures of its drug-binding domain TipAS in complexes with promothiocin A and nosiheptide, and a model of the thiostrepton complex. Drug binding induces a large transition from a partially unfolded to a globin-like structure. The structures rationalize the mechanism of promiscuous, yet specific, drug recognition: (i) a four-ring motif present in all known TipA-inducing antibiotics is recognized specifically by conserved TipAS amino acids; and (ii) the variable part of the antibiotic is accommodated within a flexible cleft that rigidifies upon drug binding. Remarkably, the identified four-ring motif is also the major interacting part of the antibiotic with the ribosome. Hence the TipA multidrug resistance mechanism is directed against the same chemical motif that inhibits protein synthesis. The observed identity of chemical motifs responsible for antibiotic function and resistance may be a general principle and could help to better define new leads for antibiotics.
authors.affiliation: Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and.
authors.forename: Judith
authors.initials: J
authors.lastname: Habazettl
authors.affiliation: Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and.
authors.forename: Martin
authors.initials: M
authors.lastname: Allan
authors.affiliation: Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and.
authors.forename: Pernille Rose
authors.initials: PR
authors.lastname: Jensen
authors.affiliation: Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Sass
authors.affiliation: Department of Microbiology and Immunology, Life Sciences Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Thompson
authors.affiliation: Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland; and stephan.grzesiek@unibas.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Grzesiek
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D019906:Nuclear Magnetic Resonance, Biomolecular; D013883:Thiostrepton / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013883:Thiostrepton
keywords: antibiotic recognition; protein dynamics; solution NMR; thiopeptides; transcriptional regulation