6DNU

Crystal Structure of Neisseria meningitidis DsbD c-terminal domain in the oxidised form

Summary for 6DNU

• Entry DOI: 10.2210/pdb6dnu/pdb
• Descriptor: Thiol:disulfide interchange protein DsbD, HEXAETHYLENE GLYCOL (3 entities in total)
• Functional Keywords: disulphide reductase, dsb proteins, oxidoreductase
• Biological source: Neisseria meningitidis (strain alpha14)
• Total number of polymer chains: 2
• Total formula weight: 28384.12

Authors

Heras, B.,Smith, R.P.,Paxman, J.J. (deposition date: 2018-06-07, release date: 2018-09-12, Last modification date: 2018-11-07)

Primary citation

Smith, R.P.,Mohanty, B.,Mowlaboccus, S.,Paxman, J.J.,Williams, M.L.,Headey, S.J.,Wang, G.,Subedi, P.,Doak, B.C.,Kahler, C.M.,Scanlon, M.J.,Heras, B.
Structural and biochemical insights into the disulfide reductase mechanism of DsbD, an essential enzyme for neisserial pathogens.
J. Biol. Chem., 293:16559-16571, 2018

PubMed Abstract: The worldwide incidence of neisserial infections, particularly gonococcal infections, is increasingly associated with antibiotic-resistant strains. In particular, extensively drug-resistant strains that are resistant to third-generation cephalosporins are a major public health concern. There is a pressing clinical need to identify new targets for the development of antibiotics effective against -specific processes. In this study, we report that the bacterial disulfide reductase DsbD is highly prevalent and conserved among spp. and that this enzyme is essential for survival of DsbD is a membrane-bound protein that consists of two periplasmic domains, n-DsbD and c-DsbD, which flank the transmembrane domain t-DsbD. In this work, we show that the two functionally essential periplasmic domains of DsbD catalyze electron transfer reactions through unidirectional interdomain interactions, from reduced c-DsbD to oxidized n-DsbD, and that this process is not dictated by their redox potentials. Structural characterization of the n- and c-DsbD domains in both redox states provides evidence that steric hindrance reduces interactions between the two periplasmic domains when n-DsbD is reduced, thereby preventing a futile redox cycle. Finally, we propose a conserved mechanism of electron transfer for DsbD and define the residues involved in domain-domain recognition. Inhibitors of the interaction of the two DsbD domains have the potential to be developed as anti-neisserial agents.

PubMed: 30181210
DOI: 10.1074/jbc.RA118.004847

Experimental method

X-RAY DIFFRACTION (2.283 Å)