Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 10 (October 2013)


research papers



Acta Cryst. (2013). D69, 1981-1994    [ doi:10.1107/S0907444913017800 ]

Rv2969c, essential for optimal growth in Mycobacterium tuberculosis, is a DsbA-like enzyme that interacts with VKOR-derived peptides and has atypical features of DsbA-like disulfide oxidases

L. Premkumar, B. Heras, W. Duprez, P. Walden, M. Halili, F. Kurth, D. P. Fairlie and J. L. Martin

Abstract: The bacterial disulfide machinery is an attractive molecular target for developing new antibacterials because it is required for the production of multiple virulence factors. The archetypal disulfide oxidase proteins in Escherichia coli (Ec) are DsbA and DsbB, which together form a functional unit: DsbA introduces disulfides into folding proteins and DsbB reoxidizes DsbA to maintain it in the active form. In Mycobacterium tuberculosis (Mtb), no DsbB homologue is encoded but a functionally similar but structurally divergent protein, MtbVKOR, has been identified. Here, the Mtb protein Rv2969c is investigated and it is shown that it is the DsbA-like partner protein of MtbVKOR. It is found that it has the characteristic redox features of a DsbA-like protein: a highly acidic catalytic cysteine, a highly oxidizing potential and a destabilizing active-site disulfide bond. Rv2969c also has peptide-oxidizing activity and recognizes peptide segments derived from the periplasmic loops of MtbVKOR. Unlike the archetypal EcDsbA enzyme, Rv2969c has little or no activity in disulfide-reducing and disulfide-isomerase assays. The crystal structure of Rv2969c reveals a canonical DsbA fold comprising a thioredoxin domain with an embedded helical domain. However, Rv2969c diverges considerably from other DsbAs, including having an additional C-terminal helix (H8) that may restrain the mobility of the catalytic helix H1. The enzyme is also characterized by a very shallow hydrophobic binding surface and a negative electrostatic surface potential surrounding the catalytic cysteine. The structure of Rv2969c was also used to model the structure of a paralogous DsbA-like domain of the Ser/Thr protein kinase PknE. Together, these results show that Rv2969c is a DsbA-like protein with unique properties and a limited substrate-binding specificity.

PDB reference: 4k6x

Keywords: DsbA; VKOR; DsbB; antibacterial target; oxidative folding; virulence; thioredoxin.


pdfdisplay filedownload file

Portable Document Format (PDF) file
[ doi:10.1107/S0907444913017800/tz5033sup1.pdf ]
Supplementary material


Notes:

To open or display or play some files, you may need to set your browser up to use the appropriate software. See the full list of file types for an explanation of the different file types and their related mime types and, where available links to sites from where the appropriate software may be obtained.

The download button will force most browsers to prompt for a file name to store the data on your hard disk.

Where possible, images are represented by thumbnails.

 bibliographic record in  format

  Find reference:   Volume   Page   
  Search:     From   to      Advanced search

Copyright © International Union of Crystallography
IUCr Webmaster