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structural characterization of iron uptake from human transferrin

人转铁蛋白吸收铁的结构特征

基本信息

批准号：
8741420
负责人：
Susan Buchanan
金额：
$ 61.73万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8741420
关键词：
Amino Acids Anions Bacteria Bacterial Infections Bacterial Meningitis Bacterial Outer Membrane Proteins Binding Binding Proteins Biochemical Biochemistry Cells Complex Data Detection Development Disease Drug Design Electron Microscopy Excision Family member Genetic Goals Gonorrhea Gram-Negative Bacteria Haptoglobins Hemoglobin Human In Transferrin Individual Iron Iron-Binding Proteins Lactoferrin Learning Length Light Liquid substance Lobe Manuscripts Mediating Membrane Membrane Proteins Meningococcal Infections Metals Methods Modeling N-terminal Nature Neisseria Neisseria gonorrhoeae Neisseria meningitidis Plasma Proteins Process Protein Binding Proteins Publishing Research Personnel Resolution Roentgen Rays Role Route Sequence Homology Serum Specificity Structure Techniques Transferrin Transferrin-Binding Protein A Transferrin-Binding Protein B Transferrin-Binding Proteins Vaccines Work X-Ray Crystallography bacterial resistance base drug development follow-up improved innovation insight molecular dynamics pathogen pathogenic bacteria protein complex protein structure receptor therapeutic development uptake vaccine development

项目摘要

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

背景资料：奈瑟氏菌是感染人类的细菌病原体，引起细菌性脑膜炎和淋病。细菌需要铁来生存，并直接从人类蛋白质中获得。奈瑟氏球菌具有外膜蛋白TbpA和辅助受体蛋白TbpB，它们一起可以从称为转铁蛋白的人血浆蛋白中提取铁。使用X射线晶体学，电子显微镜，小角X射线散射，生物化学和分子动力学模拟的综合方法，我们阐明了铁清除机制，并在2012年发表在Nature文章中。创新：这是细菌外膜蛋白与其全长人类靶蛋白结合的第一个原子分辨率结构。通过使用高，中，低分辨率结构技术与计算和生物化学方法相结合的方法，我们能够扩展几个晶体结构的静态快照，形成一个更大的，完整的铁进口过程的三维动态模型。这项工作回答了该领域的所有重要问题，定义了奈瑟氏球菌对人类转铁蛋白的特异性，推导出细菌如何提取紧密结合的铁，并显示了辅助受体如何提高铁吸收的效率。重要性：从结构/功能分析中获得的信息可能有助于设计细菌性脑膜炎和淋病的药物和疫苗。目前还没有预防淋球菌感染的疫苗。虽然存在细菌性脑膜炎的疫苗，但它们具有局限性，不能保护所有菌株。随着最近检测到泛耐药菌株，迫切需要开发针对这些病原体的更好对策。后续行动：我们与淋病奈瑟氏菌的主要研究者共同撰写了一篇综述，将我们工作中的结构见解与多年来收集的遗传和生化数据联合收割机结合起来。我们在N.脑膜炎球菌感染揭示了脑膜炎球菌和淋球菌感染，并将作为使用外膜蛋白成分的药物和疫苗开发的基础。此外，我们与同一合作者共同撰写了第二份手稿，以讨论转铁蛋白结合蛋白和乳铁蛋白结合蛋白的相似性和差异，其中没有可用的结构数据。 *Noinaj，N.，北卡罗来纳州伊斯利，Oke，M.，Mizuno，N.，甘巴特，J.，Boura，E.，Steere，A.，Zak，O.，Aisen，P.，Tajkhorshid，E.M.，埃文斯河，巴西-地Gorringe，A.，Mason，A.B.，Steven，A. & Buchanan，S.K.（2012年）。致病性奈瑟氏菌的铁输入机制。Nature 483，53-58. PMCID：PMC3292680