4tky
The complex structure of E. coli DsbA bound to a peptide at the DsbA/DsbB interface
Structural highlights
FunctionDSBA_ECOLI Required for disulfide bond formation in some periplasmic proteins such as PhoA or OmpA. Acts by transferring its disulfide bond to other proteins and is reduced in the process. DsbA is reoxidized by DsbB. Required for pilus biogenesis. PhoP-regulated transcription is redox-sensitive, being activated when the periplasm becomes more reducing (deletion of dsbA/dsbB, treatment with dithiothreitol). MgrB acts between DsbA/DsbB and PhoP/PhoQ in this pathway.[1] [2] Publication Abstract from PubMedOne approach to address antibiotic resistance is to develop drugs that interfere with bacterial virulence. A master regulator of virulence in Gram-negative bacteria is the oxidative folding machinery comprising DsbA and DsbB. A crystal structure at 2.5 A resolution is reported here for Escherichia coli DsbA complexed with PFATCDS, a heptapeptide derived from the partner protein Escherichia coli DsbB. Details of the peptide binding mode and binding site provide valuable clues for inhibitor design. Structure-activity relationships for 30 analogues were used to produce short peptides with a cysteine that bind tightly to EcDsbA (Kd = 2.0 +/- 0.3 muM) and inhibit its activity (IC50 = 5.1 +/- 1.1 muM). The most potent inhibitor does not bind to or inhibit human thioredoxin that shares a similar active site. This finding suggests that small molecule inhibitors can be designed to exploit a key interaction of EcDsbA, as the basis for antivirulence agents with a novel mechanism of action. Peptide Inhibitors of the Escherichia coli DsbA Oxidative Machinery Essential for Bacterial Virulence.,Duprez W, Premkumar L, Halili MA, Lindahl F, Reid RC, Fairlie DP, Martin JL J Med Chem. 2014 Dec 18. PMID:25470204[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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