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Computational studies of membrane transport proteins

膜转运蛋白的计算研究

基本信息

批准号：
10915989
负责人：
Lucy Forrest
金额：
$ 129.59万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
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/10915989
关键词：
3-Dimensional ATP Hydrolysis Address Affect Architecture Back Behavior Betaine Binding Binding Sites Biochemical Biophysics Carrier Proteins Cell membrane Cellular Membrane Chemistry Collaborations Coupled Data Diabetes Mellitus Drug Interactions Energy-Generating Resources Environment Event Exposure to Human Genome Integral Membrane Protein Ions Light Lipid Bilayers Lipids Location Measurement Membrane Membrane Proteins Membrane Transport Proteins Mental Depression Mitochondria Molecular Molecular Conformation Movement Movement Disorders Neurotransmitters Nutrient Organism Pathway interactions Pattern Pharmacological Treatment Physiological Play Process Protein Conformation Proteins Regulation Role Shapes Side Site Specificity Structure Techniques Transmembrane Transport Work computer studies design experimental study flexibility laboratory experiment molecular dynamics natural flow novel therapeutics pyruvate carrier response serotonin transporter small molecule symporter

项目摘要

Secondary active transporters are a class of proteins found in cell membranes. They use existing differences in the concentration of molecules as a source of energy to move other substances, like nutrients or neurotransmitters, against their natural flow. This process requires the protein to change to expose a pathway that allows the substance to bind on one or other side of the membrane, in a repeating cycle called alternating access. Every organism contains dozens of different types of these transporter proteins. They have various designs, but they all have a kind of internal pattern of symmetry. Recent discoveries have come from looking at their 3D shapes, which have only been accessible in recent years. Nevertheless, to truly understand how each transporter works and how it is affected by its surroundings, we need to know more about the different shapes it can morph into and where it binds the substances it moves. Moreover, regions at the start and end of these protein that play important roles in cellular control of their transport behaviors are highly flexible and therefore require additional effort to characterize. Ongoing studies from our group have continued to investigate these questions in several different membrane proteins, including serotonin transporter SERT, the betaine symporter BetP, and mitochondrial pyruvate carrier MPC, using advanced structure prediction techniques and molecular dynamics simulations. These efforts are being carried out in collaboration with experimental laboratories, to drive understanding of the mechanism of membrane transport and regulation.

次级活性转运蛋白是在细胞膜上发现的一类蛋白质。它们利用现有的分子浓度差异作为能量来源来移动其他物质，如营养物质或神经递质，以对抗它们的自然流动。这一过程需要蛋白质改变，从而暴露出一条途径，使物质能够结合在膜的一边或另一边，在一个被称为交替进入的重复循环中。每个生物体都含有几十种不同类型的转运蛋白。它们有各种各样的设计，但它们都有一种内部对称的图案。最近的发现来自于观察它们的三维形状，这是近年来才得以实现的。然而，为了真正理解每个转运体是如何工作的，以及它是如何受到周围环境的影响的，我们需要更多地了解它可以变形成的不同形状，以及它在哪里与它所移动的物质结合。此外，这些蛋白的起始和末端在细胞控制其转运行为中起重要作用的区域是高度灵活的，因此需要额外的努力来表征。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural models of the NaPi-II sodium-phosphate cotransporters.

DOI：
10.1007/s00424-018-2197-x
发表时间：
2019-01
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
0
作者：
Fenollar-Ferrer C;Forrest LR
通讯作者：
Forrest LR

The ins and outs of vesicular monoamine transporters.

DOI：
10.1085/jgp.201711980
发表时间：
2018-05-07
期刊：
The Journal of general physiology
影响因子：
0
作者：
Yaffe D;Forrest LR;Schuldiner S
通讯作者：
Schuldiner S

Molecular Determinants of Substrate Specificity in Sodium-coupled Glutamate Transporters.

钠偶联谷氨酸转运蛋白底物特异性的分子决定因素。

DOI：
10.1074/jbc.m115.682666
发表时间：
2015
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Silverstein,Nechama;Ewers,David;Forrest,LucyR;Fahlke,Christoph;Kanner,BaruchI
通讯作者：
Kanner,BaruchI

Correction to: On the Role of a Conserved Methionine in the Na+-Coupling Mechanism of a Neurotransmitter Transporter Homolog.

更正：关于保守蛋氨酸在神经递质转运蛋白同系物的 Na 偶联机制中的作用。

DOI：
10.1007/s11064-021-03420-z
发表时间：
2022
期刊：
Neurochemical research
影响因子：
4.4
作者：
Zhou,Wenchang;Trinco,Gianluca;Slotboom,DirkJ;Forrest,LucyR;Faraldo-Gómez,JoséD
通讯作者：
Faraldo-Gómez,JoséD

Asymmetry of inverted-topology repeats in the AE1 anion exchanger suggests an elevator-like mechanism.