Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

Judith Habazettl, Martin Allan, Pernille Rose Jensen, Hans-Jurgen Sass, Charles J. Thompson, Stephan Grzesiek

Research output: Contribution to journalJournal articleResearchpeer-review

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.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number51
Pages (from-to)E5498-E5507
ISSN0027-8424
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Multidisciplinary
  • Antibiotic recognition
  • Protein dynamics
  • Solution NMR
  • Thiopeptides
  • Transcriptional regulation
  • antibiotic agent
  • drug binding protein
  • geninthiocin
  • methylsulfomycin
  • micrococcin P
  • nosiheptide
  • promoinducin
  • promothiocin A
  • radamycin
  • siomycin A
  • thiopeptin A
  • thiostrepton
  • thiotipin
  • TipA protein
  • TipAS protein
  • unclassified drug
  • antibiotic resistance
  • Article
  • heteronuclear single quantum coherence
  • multidrug resistance
  • protein conformation
  • protein structure
  • protein synthesis
  • proton nuclear magnetic resonance
  • ribosome
  • Bacteria (microorganisms)
  • Pterogyne nitens
  • Anti-Bacterial Agents
  • Bacteria
  • Bacterial Proteins
  • Drug Resistance, Multiple, Bacterial
  • Nuclear Magnetic Resonance, Biomolecular
  • Thiostrepton
  • antibiotic recognition
  • protein dynamics
  • solution NMR
  • thiopeptides
  • transcriptional regulation
  • MULTIDISCIPLINARY
  • PROMOTER INDUCING ACTIVITY
  • THIOSTREPTON-INDUCED GENE
  • LIVIDANS TIPAL PROTEIN
  • STREPTOMYCES-LIVIDANS
  • ESCHERICHIA-COLI
  • P-GLYCOPROTEIN
  • THIOPEPTIDE ANTIBIOTICS
  • TRANSCRIPTIONAL ACTIVATION
  • MICROBIAL METABOLITES
  • PROTEASOME INHIBITORS
  • drug binding
  • drug recognition
  • multidrug recognition system
  • amino acids
  • globin-like structure
  • nosiheptide 56377-79-8
  • promothiocin A 156737-05-2
  • thiostrepton complex
  • TipA 122-20-3
  • TipAS drug-binding domain
  • 10060, Biochemistry studies - General
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 12512, Pathology - Therapy
  • 22002, Pharmacology - General
  • 38504, Chemotherapy - Antibacterial agents
  • antibiotic therapy therapeutic and prophylactic techniques, clinical techniques
  • 1ASH Protein Data Bank amino acid sequence
  • 1E9W Protein Data Bank amino acid sequence
  • 2MBZ Protein Data Bank amino acid sequence
  • 2MC0 Protein Data Bank amino acid sequence
  • 2ZJP Protein Data Bank amino acid sequence
  • 3CF5 Protein Data Bank amino acid sequence
  • Biochemistry and Molecular Biophysics
  • Pharmacology
  • PNAS Plus
  • Biological Sciences
  • Biochemistry

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