structural characterization of iron uptake from human transferrin

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Background: Neisseria are bacterial pathogens that infect humans, causing bacterial meningitis and gonorrhea. The bacteria require iron for survival and obtain it directly from human proteins. Neisseria have an outer membrane protein, TbpA, and a co-receptor protein, TbpB, which together can extract the iron from a human plasma protein called transferrin. Using a combined approach of X-ray crystallography, electron microscopy, small angle X-ray scattering, biochemistry, and molecular dynamics simulations, we elucidated the iron-scavenging mechanismand published that body of work in a Nature article in 2012*. Innovation: This is the first atomic resolution structure of a bacterial outer membrane protein bound to its full-length human target protein. By using an approach that combined high, medium, and low resolution structural techniques with computational and biochemical methods, we were able to extend the static snapshots of several crystal structures to form a larger, three dimensional dynamic model of the complete iron import process. This work answered all of the important questions in the field, defining the neisserial specificity for human transferrin, deducing how the bacterium extracts tightly bound iron, and showing how the co-receptor improves the efficiency of iron uptake. Significance: The information learned from the structure/function analysis may assist the design of drugs and vaccines for bacterial meningitis and gonorrhea. There are currently no vaccines to protect against gonococcal infections. Although vaccines exist for bacterial meningitis, they have limitations and do not protect against all strains. With the recent detection of pan-resistant bacterial strains, there is an urgent need to development better countermeasures against these pathogens. Follow up: We coauthored a review with a leading investigator on Neisseria gonorrhea to combine the structural insights from our work with the genetic and biochemical data gathered over many years. Our work in N. menigitidis sheds light on both meningococcal and gonococcal infections and will serve as a basis for drug and vaccine developments using outer membrane protein components. Furthermore, we coauthored a second manuscript with the same collaborator to discuss the similarities and differences for the transferrin binding proteins and lactoferrin binding proteins, for which there is no structural data available. *Noinaj, N., Easley, N.C., Oke, M., Mizuno, N., Gumbart, J., Boura, E., Steere, A., Zak, O., Aisen, P., Tajkhorshid, E.M., Evans, R., Gorringe, A., Mason, A.B., Steven, A. & Buchanan, S.K. (2012). The iron import machinery from pathogenic Neisseria. Nature 483, 53-58. PMCID:PMC3292680