4TKY

The complex structure of E. coli DsbA bound to a peptide at the DsbA/DsbB interface

Summary for 4TKY

• Entry DOI: 10.2210/pdb4tky/pdb
• Descriptor: Thiol:disulfide interchange protein DsbA, PRO-PHE-ALA-THR-CYS-ASP-SER (3 entities in total)
• Functional Keywords: dsba, dsbb, dithiol oxidase, complex, dsba/dsbb, peptide inhibitor, thioredoxin-related protein, oxidoreductase-peptide inhibitor complex, oxidoreductase/peptide inhibitor
• Biological source: Escherichia coli K-12; More
• Total number of polymer chains: 8
• Total formula weight: 88351.92

Authors

Premkumar, L.,Martin, J.L. (deposition date: 2014-05-28, release date: 2015-01-14, Last modification date: 2024-12-25)

Primary citation

Duprez, W.,Premkumar, L.,Halili, M.A.,Lindahl, F.,Reid, R.C.,Fairlie, D.P.,Martin, J.L.
Peptide Inhibitors of the Escherichia coli DsbA Oxidative Machinery Essential for Bacterial Virulence.
J.Med.Chem., 58:577-587, 2015

PubMed Abstract: One 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 Å 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 μM) and inhibit its activity (IC50 = 5.1 ± 1.1 μM). 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.

PubMed: 25470204
DOI: 10.1021/jm500955s

Experimental method

X-RAY DIFFRACTION (2.5 Å)