Structural and biochemical characterisation of Chlamydia trachomatis DsbA reveals a cysteine-rich and weakly oxidising oxidoreductase

S Christensen1, M Grøftenhauge1, K Byriel1, B Heras2, R McMahon1 and JL Martin1

  1. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland 4072, Australia
  2. La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia

The rise of antibiotic drug resistance is undermining our ability to treat an increasing range of bacterial infections and is a huge threat to public health worldwide (1) Disulfide bonds provide structural bracing to numerous proteins including those involved in bacterial pathogenesis (2). The bacterial disulfide bond protein DsbA catalyses the formation of disulfide bonds and is thus a potential target for drug development. The focus of this study is DsbA from the obligate intracellular human pathogen Chlamydia trachomatis (CtDsbA). CtDsbA stands out from other DsbA enzymes by having an uneven number of cysteines, an additional disulfide bond as well as an uncommon dipeptide sequence in the catalytic motif (CSAC). We report the 2.7 Å crystal structure of CtDsbA revealing a typical DsbA fold. This study confirms that CtDsbA has oxidase activity and redox properties similar to other DsbAs. However, DsbA is a significantly weaker oxidase than other DsbAs studied. This can be explained by a lack of factors stabilizing the active site nucleophilic thiolate. The characterization of CtDsbA contributes to the broader understanding of the redox properties of DsbA proteins and supports ongoing efforts to develop inhibitors of these proteins. (1) Beating bad bugs. Nat Rev Drug Discov, 2010. 9(9): p. 663. (2) Bardwell, J.C., K. McGovern, and J. Beckwith, Identification of a protein required for disulfide bond formation in vivo. Cell, 1991. 67(3): p. 581-9.