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Structures of the TetR-like simocyclinone efflux pump repressor, SimR, and the mechanism of ligand-mediated derepression

DOI: 10.1016/j.jmb.2011.02.035 DOI Help
PMID: 21354180 PMID Help

Authors: Tung B. K. Le (University of East Anglia) , Clare E. M. Stevenson (John Innes Centre) , Hans-Peter Fiedler (Eberhard-Karls-Universität Tübingen) , Anthony Maxwell (John Innes Centre) , David M. Lawson (John Innes Centre) , Mark J. Buttner (John Innes Centre)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: February 2011

Abstract: Simocyclinone D8, a potent DNA gyrase inhibitor produced by Streptomyces antibioticus, is exported from the producing organism by the SimX efflux pump. The expression of simX is under the control of SimR, a member of the TetR family of transcriptional regulators (TFRs). SimR represses simX transcription by binding to operators in the intergenic region between simR and simX. Previously we have shown that the mature antibiotic, simocyclinone D8, or its biosynthetic intermediate, simocyclinone C4, can dissociate SimR from its operators, leading to derepression of simX and export of simocyclinone D8 from the cell. This provides a mechanism that couples the biosynthesis of the antibiotic to its export. Here we report crystal structures of SimR alone and in complex with either simocyclinone D8 or simocyclinone C4. The ligand-binding pocket is unusual compared to those of other characterised TFRs: the structures show an extensive ligand-binding pocket spanning both monomers in the functional dimeric unit, with the aminocoumarin moiety of simocyclinone D8 buried in the protein core, while the angucyclic polyketide moiety is partially exposed to bulk solvent. Through comparisons of the structures, we postulate a derepression mechanism for SimR that invokes rigid body motions of the subunits relative to one another, coupled with a putative locking mechanism to restrict further conformational change.

Journal Keywords: crystal structures; transcriptional regulation; antibiotic resistance; antibiotic biosynthesis; Streptomyces

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 02/03/2011 15:24

Discipline Tags:

Pathogens Antibiotic Resistance Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)