Project 3

项目3

• 批准号: 8151962
• 负责人: CHARLES R SANDERS
• 金额: $ 46.91万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8151962
• 关键词: Biological; Cholesterol; Detergents; Disease; Ethers; Head; Integral Membrane Protein; Link; Lipids; Lysophospholipids; Measurement; Membrane; Membrane Proteins; Methods; Micelles; Mole the mammal; Molecular Chaperones; Molecular Conformation; Organism; Phosphotransferases; Polymers; Preparation; Relative (related person); Relaxation; Resources; Sampling; Solubility; Solutions; Source; Staging; Streptococcus mutans; Structure; System; Testing; Work; base; cholesterol analog; design; dimer; human PMP22 protein; membrane model; mimetics; monomer; novel; protein structure; restraint; structural biology; structural genomics; surfactant

3.3. Background and Significance 3.3.1. There is a compelling need for novel model membrane media that are optimized for MP structural biology. The vast majority of MP structures determined to date by either NMR or crystallographic methods were determined using classical detergent as the model membrane media. Unfortunately, even mild detergents destabilize MPs relative to their stability in native membranes. Moreover, many of the mildest detergents (such as the alkyl maltoside) routinely fail to yield high quality NMR spectra. More native-like media, such as detergent-lipid mixed micelles or bicelles sometimes offer advantages, but also have drawbacks. Moreover, while membranes from higher organisms almost always contain a considerable mole fraction of cholesterol, very little work has been carried out to establish NMR-compatible media that contain cholesterol, in part because of its very low solubility in detergent solutions. It is clear that there is a need to expand the range of membrane-mimetic media that are available. We propose to design, synthesize (through Core B) and test new surfactants for use in structural biological studies of MPs. We also will test surfactants and cholesterol analogs that have recently been commercialized but not yet well tested.

3.3。背景和意义 3.3.1。对MP结构生物学优化的新型模型膜培养基的需求迫切需要。使用经典洗涤剂作为模型膜培养基确定了确定迄今通过NMR或晶体学方法确定的绝大多数MP结构。不幸的是，即使是温和的洗涤剂，也相对于其在本地膜中的稳定性而破坏了MPS的稳定稳定。此外，许多最温和的洗涤剂（例如麦芽糖苷）通常无法产生高质量的NMR光谱。更类似原生的媒体，例如洗涤剂脂混合胶束或双丝胶质，有时会带来优势，但也有缺点。此外，虽然来自较高生物体的膜几乎总是含有相当大的胆固醇，但几乎没有进行建立含有NMR兼容培养基的胆固醇的工作，部分原因是其在洗涤剂溶液中的溶解度非常低。显然，有必要扩大可用的膜模拟媒体的范围。我们建议设计，合成（通过核心B）并测试新的表面活性剂，以用于MPS结构生物学研究。我们还将测试表面活性剂 最近已经商业化但尚未经过良好测试的胆固醇类似物。