title: Homology modelling of transferrin-binding protein A from Neisseria meningitidis.
abstract: 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 beta-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.
authors.affiliation: Metalloprotein Research Group, Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Oakhill
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Sutton
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gorringe
authors.forename: Robert W
authors.initials: RW
authors.lastname: Evans
mesh_terms: D000595:Amino Acid Sequence; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D000939:Epitopes; D004926:Escherichia coli / Q000378:metabolism; D007501:Iron; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D017262:Siderophores / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D033881:Transferrin-Binding Protein A / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D000939:Epitopes; D008024:Ligands; D011956:Receptors, Cell Surface; D017262:Siderophores; D014168:Transferrin; D033881:Transferrin-Binding Protein A; C035902:siderophore receptors; D007501:Iron