The FUR protein (ferric uptake regulator) is an iron-dependent global 
transcriptional regulator. Specific to bacteria, FUR is an attractive 
antibacterial target since virulence is correlated to iron bioavailability. 
Recently, four anti-FUR peptide aptamers, composed of 13 amino acid variable 
loops inserted into a thioredoxinA scaffold, were identified, which were able to 
interact with Escherichia coli FUR (EcFUR), inhibit its binding to DNA and to 
decrease the virulence of pathogenic E. coli in a fly infection model. The first 
characterization of anti-FUR linear peptides (pF1 6 to 13 amino acids) derived 
from the variable part of the F1 anti-FUR peptide aptamer is described herein. 
Theoretical and experimental approaches, in original combination, were used to 
study interactions of these peptides with FUR in order to understand their 
mechanism of inhibition. After modeling EcFUR by homology, docking with Autodock 
was combined with molecular dynamics simulations in implicit solvent to take 
into account the flexibility of the partners. All calculations were 
cross-checked either with other programs or with experimental data. As a result, 
reliable structures of EcFUR and its complex with pF1 are given and an 
inhibition pocket formed by the groove between the two FUR subunits is proposed. 
The location of the pocket was validated through experimental mutation of key 
EcFUR residues at the site of proposed peptide interaction. Cyclisation of pF1, 
mimicking the peptide constraint in F1, improved inhibition. The details of the 
interactions between peptide and protein were analyzed and a mechanism of 
inhibition of these anti-FUR molecules is proposed.