Comparative sequence, structure and redox analyses of Klebsiella pneumoniae DsbA show that anti-virulence target DsbA enzymes fall into distinct classes

Kurth, Fabian, Rimmer, Kieran, Premkumar, Lakshmanane, Mohanty, Biswaranjan, Duprez, Wilko, Halili, Maria A., Shouldice, Stephen R., Heras, Begoña, Fairlie, David P., Scanlon, Martin J. and Martin, Jennifer L. (2013) Comparative sequence, structure and redox analyses of Klebsiella pneumoniae DsbA show that anti-virulence target DsbA enzymes fall into distinct classes. PloS One, 8 11: e80210.1-e80210.15. doi:10.1371/journal.pone.0080210


Author Kurth, Fabian
Rimmer, Kieran
Premkumar, Lakshmanane
Mohanty, Biswaranjan
Duprez, Wilko
Halili, Maria A.
Shouldice, Stephen R.
Heras, Begoña
Fairlie, David P.
Scanlon, Martin J.
Martin, Jennifer L.
Title Comparative sequence, structure and redox analyses of Klebsiella pneumoniae DsbA show that anti-virulence target DsbA enzymes fall into distinct classes
Formatted title
Comparative sequence, structure and redox analyses of Klebsiella pneumoniae DsbA show that anti-virulence target DsbA enzymes fall into distinct classes
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-11-14
Sub-type Article (original research)
DOI 10.1371/journal.pone.0080210
Open Access Status DOI
Volume 8
Issue 11
Start page e80210.1
End page e80210.15
Total pages 15
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2014
Language eng
Formatted abstract
Bacterial DsbA enzymes catalyze oxidative folding of virulence factors, and have been identified as targets for antivirulence drugs. However, DsbA enzymes characterized to date exhibit a wide spectrum of redox properties and divergent structural features compared to the prototypical DsbA enzyme of Escherichia coli DsbA (EcDsbA). Nonetheless, sequence analysis shows that DsbAs are more highly conserved than their known substrate virulence factors, highlighting the potential to inhibit virulence across a range of organisms by targeting DsbA. For example, Salmonella enterica typhimurium (SeDsbA, 86 % sequence identity to EcDsbA) shares almost identical structural, surface and redox properties. Using comparative sequence and structure analysis we predicted that five other bacterial DsbAs would share these properties. To confirm this, we characterized Klebsiella pneumoniae DsbA (KpDsbA, 81 % identity to EcDsbA). As expected, the redox properties, structure and surface features (from crystal and NMR data) of KpDsbA were almost identical to those of EcDsbA and SeDsbA. Moreover, KpDsbA and EcDsbA bind peptides derived from their respective DsbBs with almost equal affinity, supporting the notion that compounds designed to inhibit EcDsbA will also inhibit KpDsbA. Taken together, our data show that DsbAs fall into different classes; that DsbAs within a class may be predicted by sequence analysis of binding loops; that DsbAs within a class are able to complement one another in vivo and that compounds designed to inhibit EcDsbA are likely to inhibit DsbAs within the same class.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 29 Nov 2013, 11:53:12 EST by Prem Lakshmanane on behalf of Chemistry, Department of