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PEDS Advance Access originally published online on April 8, 2005
Protein Engineering Design and Selection 2005 18(5):221-228; doi:10.1093/protein/gzi024
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Homology modelling of transferrin-binding protein A from Neisseria meningitidis

Jonathan S. Oakhill1,2, Brian J. Sutton1, Andrew R. Gorringe3 and Robert W. Evans1,4

1Metalloprotein Research Group, Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL and 3Health Protection Agency, Salisbury SP4 0JG, UK 2Present address: Division of Life Sciences, King's College London, Franklin-Wilkins Building, Waterloo, London SE1 9NH, UK

4 To whom correspondence should be addressed. E-mail: robert.evans{at}kcl.ac.uk

Neisseria meningitidis, a causative agent of bacterial meningitis, obtains transferrin-bound iron by expressing two outer membrane located transferrin-binding proteins, TbpA and TbpB. TbpA is thought to be an integral outer membrane pore that facilitates iron uptake. Evidence suggests that TbpA is a useful antigen for inclusion in a vaccine effective against meningococcal disease, hence the identification of regions involved in ligand binding is of paramount importance to design strategies to block uptake of iron. The protein shares sequence and functional similarities to the Escherichia coli siderophore receptors FepA and FhuA, whose structures have been determined. These receptors are composed of two domains, a 22-stranded ß-barrel and an N-terminal plug region that sits within the barrel and occludes the transmembrane pore. A three-dimensional TbpA model was constructed using FepA and FhuA structural templates, hydrophobicity analysis and homology modelling. TbpA was found to possess a similar architecture to the siderophore receptors. In addition to providing insights into the highly immunogenic nature of TbpA and allowing the prediction of potentially important ligand-binding epitopes, the model also reveals a narrow channel through its entire length. The relevance of this channel and the spatial arrangement of external loops, to the mechanism of iron translocation employed by TbpA is discussed.

Keywords: iron/meningococcal/TbpA/transferrin

Received November 11, 2004; revised March 16, 2005; accepted March 19, 2005.

Edited by Hagan Bayley


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