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Folding and Design of Beta Sheets in Membranes

膜中β片的折叠和设计

基本信息

批准号：
7759198
负责人：
WILLIAM C WIMLEY
金额：
$ 37.72万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7759198
关键词：
Algorithms Antibiotics Biological Biological Models Biomedical Engineering Biosensor Biotechnology Chlamydia Chloroplasts Databases Drug Delivery Systems Drug Design Engineering Family Figs - dietary Genome Genomics Genus Mycobacterium Goals Gram-Negative Bacteria Hemolysin Host Defense Human Integral Membrane Protein Libraries Life Lipid Bilayers Lipids Membrane Membrane Proteins Methods Mitochondria Peptide Antibiotics Peptides Proteins Proteome Proteomics Research Screening procedure Staphylococcus aureus Structure Structure-Activity Relationship System Thermodynamics Toxin Venoms Vesicle Virulence anthrax toxin antimicrobial antimicrobial peptide base beta pleated sheet combinatorial chemistry cytotoxic design driving force engineering design high throughput screening interest member pathogen peptide structure programs self assembly

项目摘要

DESCRIPTION (provided by applicant): Integral membrane proteins comprise about 25% of all genomes. Those that use the b-barrel motif comprise up to 4% of the genomes of Gram-negative bacteria, and are also present in mycobacteria, chlamydiae, mitochondria and chloroplasts. Exogenous proteins and peptides that self-assemble into b-sheets in membranes are also found in all kingdoms of life, including humans, where they are involved in pathogen virulence and host defense and in the action of many toxins and venoms. For example, the Anthrax toxin and the a-hemolysin of Staphylococcus aureus use b-barrels to permeabilize membranes. There are also many pore-forming peptide antibiotics that are predominantly b-sheet structure. In this ongoing research program we are pursuing a deeper understanding of the driving forces and structure-function relationships for the self-assembly of b-sheets in synthetic and biological membranes in order to design self-assembling b-sheet peptides that have interesting and useful structures and functions in membranes, and in order to identify b-barrel membrane proteins, predict their structure and engineer their function. The methods we are using for designing and engineering pore-forming peptides and for characterizing antimicrobial and cytotoxic activity have potentially important biotechnology applications in the fields of antibiotics, biosensors and drug delivery. These broad goals will be accomplished through the following lines of experimentation. Design new families of pore-forming peptides by screening libraries for members that self-assemble into pores in lipid bilayer membranes. Characterize the mechanism of pore formation in lipid vesicles and the structure of the peptide and cross characterize the antimicrobial activity of pore formers. Design and characterize pore-forming peptides by screening libraries for potent, broad-spectrum antimicrobial activity. Cross characterize antimicrobial peptides in vesicle-based systems to compare the determinants of structure and function in the two systems. Use combinatorial chemistry and high throughput screening to design peptides that self-assemble into membrane-spanning, protein-like b-barrel pores. Finally we will use genomics and proteomics to delineate the b-barrel proteomes of Gram-negative bacteria and validate b-barrel prediction algorithms. This information will be used to create a public database of potential outer membrane proteins

描述(申请人提供)：完整的膜蛋白约占所有基因组的25%。那些使用b-Barrel基序的细菌占革兰氏阴性细菌基因组的4%，也存在于分枝杆菌、衣原体、线粒体和叶绿体中。在细胞膜中自组装成b-折叠的外源蛋白质和多肽也存在于包括人类在内的所有生命王国中，它们参与病原体的毒力和宿主防御，以及许多毒素和毒液的作用。例如，炭疽毒素和金黄色葡萄球菌的a-溶血素使用b-桶来渗透膜。也有许多以b-折叠结构为主的成孔多肽抗生素。在这项正在进行的研究计划中，我们正在深入了解b-折叠在合成膜和生物膜中自组装的驱动力和结构-功能关系，以便设计在膜中具有有趣和有用的结构和功能的自组装b-折叠多肽，并识别b-桶膜蛋白，预测其结构和工程其功能。我们正在使用的设计和工程造孔肽以及表征抗菌和细胞毒活性的方法在抗生素、生物传感器和药物输送领域具有潜在的重要生物技术应用。这些广泛的目标将通过以下几条试验路线来实现。通过筛选在脂质双层膜中自组装成孔的成员的文库，设计新的成孔肽家族。表征脂泡中孔形成的机制和多肽的结构，并交叉表征造孔剂的抗菌活性。通过筛选有效的、广谱的抗菌活性文库，设计和表征造孔肽。交叉表征基于囊泡的系统中的抗菌肽，以比较两个系统中结构和功能的决定因素。使用组合化学和高通量筛选来设计多肽，这些多肽可以自组装成跨膜的、蛋白质样的b-桶孔。最后，我们将使用基因组学和蛋白质组学来描绘革兰氏阴性细菌的b-Barrel蛋白质组，并验证b-Barrel预测算法。这些信息将被用来创建一个潜在外膜蛋白的公共数据库

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The prediction and characterization of YshA, an unknown outer-membrane protein from Salmonella typhimurium.

DOI：
10.1016/j.bbamem.2010.09.008
发表时间：
2011-01
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Freeman TC Jr;Landry SJ;Wimley WC
通讯作者：
Wimley WC

Biomolecular engineering by combinatorial design and high-throughput screening: small, soluble peptides that permeabilize membranes.

DOI：
10.1021/ja8017863
发表时间：
2008-07-30
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Rathinakumar, Ramesh;Wimley, William C.
通讯作者：
Wimley, William C.

Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity.

DOI：
10.1021/jacs.5b10595
发表时间：
2015-12-30
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Krauson AJ;Hall OM;Fuselier T;Starr CG;Kauffman WB;Wimley WC
通讯作者：
Wimley WC

Release of dengue virus genome induced by a peptide inhibitor.

DOI：
10.1371/journal.pone.0050995
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Lok SM;Costin JM;Hrobowski YM;Hoffmann AR;Rowe DK;Kukkaro P;Holdaway H;Chipman P;Fontaine KA;Holbrook MR;Garry RF;Kostyuchenko V;Wimley WC;Isern S;Rossmann MG;Michael SF
通讯作者：
Michael SF

Spontaneous membrane-translocating peptides by orthogonal high-throughput screening.