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J Biomol Struct Dyn. 2016 Oct;34(10):2296-304. doi: 10.1080/07391102.2015.1115779. Epub 2016 Jan 6.

Structural modeling of the ExuR and UxuR transcription factors of E. coli: search for the ligands affecting their regulatory properties.

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a Institute of Cell Biophysics Russian Academy of Sciences , Institutskaya str., 3, Pushchino , Moscow Region 142290 , Russia.
b Centre for Genomic Regulation (CRG) and Universitat Pompeu Fabra (UPF) , C/Dr. Aiguader, 88, Barcelona 08003 , Spain.


Gammaproteobacteria get energy for their growth from different carbon sources using either glycolysis or alternative metabolic pathways induced in stress conditions. These metabolic switches are coordinated by complex interplay of regulatory proteins sensing concentrations of available metabolites by mechanisms yet to be understood. Here, we use two transcriptional regulators, ExuR and UxuR, controlling d-galacturonate (d-gal) and d-glucuronate metabolism in Escherichia coli, as the targets for computational search of low-molecular compounds capable to bind their ligand-binding domains. Using a flexible molecular docking, we modeled the interactions of these proteins with substrates and intermediates of glycolysis, Ashwell and Entner-Doudoroff pathways. For UxuR, the two preferred sites of ligand binding were found: one is located within the C-terminal domain, while another occupies the interdomain space. For ExuR, the only one preferred site was detected in the interdomain area. Availability of this area to different ligands suggests that, similar to the Lac repressor, the DNA-binding properties of UxuR and ExuR may be changed by repositioning of their domains. Experimental assays confirmed the ability of ligands with highest affinities to bind the regulatory proteins and affect their interaction with DNA. d-gal that is carried into the cell by the ExuT transporter appeared to be the best ligand for repressor of the exuT transcription, ExuR. For UxuR, the highest affinity was found for d-fructuronate transported by GntP, which biosynthesis is repressed by UxuR. Providing a feedback loop to balance the concentrations of different nutrients, such ligand-mediated modulation can also coordinate switching between different metabolic pathways in bacteria.


Escherichia coli; UxuR and ExuR; ligand-dependent transcriptional factors; molecular docking; sugar metabolism

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