一个ABC输送器与一个二次活跃的多药转位器域
Henrietta Venter1, Richard A Shilling, Saroj Velamakanni
1Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Nature
|December 20, 2003
概括
研究人员设计了一种截断的多药耐药性蛋白 (LmrA),其功能是作为二次活性转运器. 这表明,初级活性载体的进化起源来自二级活性系统.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 多药性耐药性 (MDR) 是医学上的一个重大挑战,通常由从细胞中挤出药物的活性运输体介导.
- 像P-glycoprotein这样的初级活性载体使用ATP水解,而二级活性载体依赖离子梯度.
- 来自Lactococcus lactis的ATP结合盒 (ABC) 载体LmrA是一种已知的初级药物排泄.
研究的目的:
- 研究ATP结合域在LmrA的运输机制中的功能作用.
- 为了确定LmrA是否可以作为二次活性载体起作用.
主要方法:
- 设计了一个缺少ATP结合域的截断LmrA蛋白.
- 在细胞系统中评估截断的LmrA的运输活动.
主要成果:
- 截断的LmrA蛋白显示出质子-乙配送活性.
- 这种运输是独立于ATP水解发生的,这表明二次活性运输.
- 工程蛋白质作为一种多药吸收系统起作用.
结论:
- 这些发现表明,LmrA是从一个二次活性载体进化而来的.
- 获得一个ATP结合域可能使得过渡到初级活性流体.
- 这为药物载体的进化途径提供了洞察力.
相关概念视频
Membrane Transporters
Transporters are essential membrane transport proteins with functions related to cell nutrition, homeostasis, communication, etc. Approximately 7% of all genes in the human genome code for transporters or transporter-related proteins.
Transporters are mainly composed of alpha-helices, built from bundles of ten or more helices traversing the plasma membrane. The solute-binding sites are located midway, where some of the helices are broken or distorted, making space for the binding site through...
Transporters are mainly composed of alpha-helices, built from bundles of ten or more helices traversing the plasma membrane. The solute-binding sites are located midway, where some of the helices are broken or distorted, making space for the binding site through...
ABC Transporters: Exporter
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
ABC Transporters: Importer
ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
Secondary Active Transport
One example of how cells use the energy contained in electrochemical gradients is demonstrated by glucose transport into cells. The ion vital to this process is sodium (Na+), which is typically present in higher concentrations extracellularly than in the cytosol. Such a concentration difference is due, in part, to the action of an enzyme "pump" embedded in the cellular membrane that actively expels Na+ from a cell. Importantly, as this pump contributes to the high concentration of...
Drug Absorption Mechanism: Carrier-Mediated Membrane Transport
Certain large, lipid-insoluble drug molecules that resemble amino acids, peptides, or glucose, require specialized carrier proteins to facilitate their diffusion across cell membranes. This transport can occur through either facilitated diffusion, which does not require energy input, or active transport, which does require energy input.
Facilitated diffusion is a passive process that utilizes human Solute Carrier (SLC) transporters. These transporters bind to the drug, undergo structural...
Facilitated diffusion is a passive process that utilizes human Solute Carrier (SLC) transporters. These transporters bind to the drug, undergo structural...
Active Transport
Active transport is a critical biological process that allows cells to move solutes against an electrochemical gradient. This process requires direct energy input and is characterized by its selectivity, saturability, and susceptibility to competitive inhibition.
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...


