Conformational change in NSS transporters

NSS转运蛋白的构象变化

• 批准号: 9364079
• 负责人: GARY W RUDNICK
• 金额: $ 64.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364079
• 关键词: Affinity; Amination; Amines; Amino Acid Transporter; Amino Acids; Animals; Binding; Binding Sites; Biochemical; Biological; Biophysics; Brain; Carrier Proteins; Cell membrane; Cells; Coupled; Couples; Coupling; Crystallization; Cysteine; Diet; Disease; Drosophila genus; Family; Family member; Glycine; Goals; Health; Human; Intestines; Investigation; Iodides; Ion Cotransport; Ions; Kidney; Ligand Binding; Ligands; Link; Measurement; Mediating; Membrane; Membrane Transport Proteins; Minerals; Molecular Conformation; Molecular Structure; Monitor; Movement; Mutation; Nature; Neurons; Neurotransmitters; Occupations; Pathway interactions; Peripheral; Physiological Processes; Process; Prokaryotic Cells; Proteins; Pump; Resolution; Role; Sampling; Serotonin; Side; Site; Sodium; Structure; Sugar Acids; Testing; Thyroid Gland; Transport Process; Work; antiport; base; conformational conversion; design; driving force; glycine transporter; inhibitor/antagonist; insight; molecular dynamics; monoamine; mutant; neurotransmitter reuptake; novel; nutrient absorption; protein folding; protein structure; protein transport; radioligand; response; serotonin transporter; single-molecule FRET; small molecule; solute; symporter; uptake

Abstract Our goal is to understand the mechanism by which a large family of transport proteins moves small molecules and ions across biological membranes. In recent years it has become apparent that many families of transport proteins are related at the structural level. The transporter proteins are responsible for moving a wide variety of substrate molecules across cell membranes. They mediate neurotransmitter re-uptake in the brain, sugar and amino acid transport in kidney and intestine, iodide transport in thyroid, and many other important transport processes that are critically important in health and disease. These transporter families are all based on a protein fold containing two structurally similar repeats in opposite orientations relative to the membrane. Recent structural evidence indicates that transport requires a conformational change in which a 4-helix bundle rearranges within the protein structure. However, the ability of these transporters to accumulate substrates within the cell using the coupled movement of ions is a separate issue not addressed by previous studies. The specific aims of this project are to use biochemical, biophysical and computational approaches to test proposed mechanisms, and to understand how binding of substrate and ions can trigger conformational changes relating to the movement of the bundle and the consequent opening and closing of permeation pathways.

摘要 我们的目标是了解一个大家族的转运蛋白移动的机制 小分子和离子穿过生物膜。近年来， 许多转运蛋白家族在结构水平上是相关的。传送器 蛋白质负责在细胞内移动各种底物分子 膜。它们介导大脑中神经递质、糖和氨基酸的重新吸收 肾脏和肠道中的碘转运，甲状腺中的碘转运，以及许多其他重要的 对健康和疾病至关重要的运输过程。这些运输机 家族都是基于一个蛋白质折叠，包含两个结构相似的重复序列， 相对于膜的方向。最近的结构证据表明， 需要构象变化，其中4-螺旋束在蛋白质内重排 结构然而，这些转运蛋白在细胞内积累底物的能力 使用离子的耦合运动是先前研究没有解决的单独问题。的 该项目的具体目标是利用生物化学、生物物理和计算方法 测试提出的机制，并了解底物和离子的结合如何触发 与纤维束的运动和随后的打开有关的构象变化 以及渗透途径的关闭。