4WF5

Crystal structure of E.Coli DsbA soaked with compound 4

Summary for 4WF5

• Entry DOI: 10.2210/pdb4wf5/pdb
• Related: 1FVK 4WET 4WEY 4WF4
• Descriptor: Thiol:disulfide interchange protein, 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid, COPPER (II) ION, ... (6 entities in total)
• Functional Keywords: disulfide oxidoreductase, redox protein, dsba, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Escherichia coli BL21(DE3)
• Total number of polymer chains: 2
• Total formula weight: 43102.27

Authors

Adams, L.A.,Sharma, P.,Mohanty, B.,Ilyichova, O.V.,Mulcair, M.D.,Williams, M.L.,Gleeson, E.C.,Totsika, M.,Doak, B.C.,Caria, S.,Rimmer, K.,Shouldice, S.R.,Vazirani, M.,Headey, S.J.,Plumb, B.R.,Martin, J.L.,Heras, B.,Simpson, J.S.,Scanlon, M.J. (deposition date: 2014-09-12, release date: 2015-01-21, Last modification date: 2024-11-13)

Primary citation

Adams, L.A.,Sharma, P.,Mohanty, B.,Ilyichova, O.V.,Mulcair, M.D.,Williams, M.L.,Gleeson, E.C.,Totsika, M.,Doak, B.C.,Caria, S.,Rimmer, K.,Horne, J.,Shouldice, S.R.,Vazirani, M.,Headey, S.J.,Plumb, B.R.,Martin, J.L.,Heras, B.,Simpson, J.S.,Scanlon, M.J.
Application of Fragment-Based Screening to the Design of Inhibitors of Escherichia coli DsbA.
Angew.Chem.Int.Ed.Engl., 54:2179-2184, 2015

PubMed Abstract: The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.

PubMed: 25556635
DOI: 10.1002/anie.201410341

Experimental method

X-RAY DIFFRACTION (1.45 Å)