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Title: Loop-to-helix transition in the structure of multidrug regulator AcrR at the entrance of the drug-binding cavity

Multidrug transcription regulator AcrR from Salmonella enterica subsp. enterica serovar Typhimurium str. LT2 belongs to the tetracycline repressor family, one of the largest groups of bacterial transcription factors. The crystal structure of dimeric AcrR was determined and refined to 1.56 Å resolution. The tertiary and quaternary structures of AcrR are similar to those of its homologs. The multidrug binding site was identified based on structural alignment with homologous proteins and has a di(hydroxyethyl)ether molecule bound. Residues from helices a4 and a7 shape the entry into this binding site. The structure of AcrR reveals that the extended helical conformation of helix a4 is stabilized by the hydrogen bond between Glu67 (helix a4) and Gln130 (helix a7). Based on the structural comparison with the closest homolog structure, the Escherichia coli AcrR, we propose that this hydrogen bond is responsible for control of the loop-to-helix transition within helix a4. This local conformational switch of helix a4 may be a key step in accessing the multidrug binding site and securing ligands at the binding site. Solution smallmolecule binding studies suggest that AcrR binds ligands with their core chemical structure resembling the tetracyclic ring of cholesterol.
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Publication Date:
OSTI Identifier:
DOE Contract Number:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Structural Biology; Journal Volume: 194; Journal Issue: 1
Research Org:
Argonne National Laboratory (ANL)
Sponsoring Org:
National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID); USDOE Office of Science - Office of Biological and Environmental Research
Country of Publication:
United States
Loop-to-helix transition; Multidrug resistance; TetR/AcrR; Transcription regulator