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

摘要

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 angstrom 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 alpha 4 and alpha 7 shape the entry into this binding site. The structure of AcrR reveals that the extended helical conformation of helix alpha 4 is stabilized by the hydrogen bond between Glu67 (helix alpha 4) and Gln130 (helix alpha 7). 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 alpha 4. This local conformational switch of helix alpha 4 may be a key step in accessing the multidrug binding site and securing ligands at the binding site. Solution small molecule binding studies suggest that AcrR binds ligands with their core chemical structure resembling the tetracyclic ring of cholesterol. (C) 2016 Published by Elsevier Inc.