Structural characterisation of Tpx from yersinia pseudotuberculosis reveals insights into the binding of salicylidene acylhydrazide compounds

Gabrielsen, M. , Beckham, K.S., Feher, V.A., Zetterstrom, C.E., Wang, D., Muller, S., Elofsson, M., Amaro, R.E., Byron, O. and Roe, A.J. (2012) Structural characterisation of Tpx from yersinia pseudotuberculosis reveals insights into the binding of salicylidene acylhydrazide compounds. PLoS ONE, 7(2), e32217. (doi: 10.1371/journal.pone.0032217) (PMID:22384182) (PMCID:PMC3288085)

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Abstract

Thiol peroxidase, Tpx, has been shown to be a target protein of the salicylidene acylhydrazide class of antivirulence compounds. In this study we present the crystal structures of Tpx from Y. pseudotuberculosis (ypTpx) in the oxidised and reduced states, together with the structure of the C61S mutant. The structures solved are consistent with previously solved atypical 2-Cys thiol peroxidases, including that for “forced” reduced states using the C61S mutant. In addition, by investigating the solution structure of ypTpx using small angle X-ray scattering (SAXS), we have confirmed that reduced state ypTpx in solution is a homodimer. The solution structure also reveals flexibility around the dimer interface. Notably, the conformational changes observed between the redox states at the catalytic triad and at the dimer interface have implications for substrate and inhibitor binding. The structural data were used to model the binding of two salicylidene acylhydrazide compounds to the oxidised structure of ypTpx. Overall, the study provides insights into the binding of the salicylidene acylhydrazides to ypTpx, aiding our long-term strategy to understand the mode of action of this class of compounds.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wang, Mr Dai and Muller, Professor Sylke and Gabrielsen, Dr Mads and Roe, Professor Andrew and Byron, Professor Olwyn
Authors: Gabrielsen, M., Beckham, K.S., Feher, V.A., Zetterstrom, C.E., Wang, D., Muller, S., Elofsson, M., Amaro, R.E., Byron, O., and Roe, A.J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Published Online:27 February 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in PLoS One 7(2):e32217
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
491441A biochemical and molecular analysis of the YhaO membrane protein in Escherichia coli O157:H7Andrew RoeBiotechnology and Biological Sciences Research Council (BBSRC)BB/G011389/1III - BACTERIOLOGY