F610A突变对AcrB输送器中基质挤出的影响:通过分子动力学模拟的解释和理由
Attilio V Vargiu1, Francesca Collu, Robert Schulz
1CNR-IOM, Unità SLACS, S.P. Monserrato-Sestu Km 0.700, I-09042 Monserrato (CA), Italy. vargiu@dsf.unica.it
Journal of the American Chemical Society
|June 29, 2011
概括
大肠杆菌的AcrB载体中的F610A突变阻碍了多克索鲁比辛的挤出,揭示了对多药物耐药性至关重要的微妙相互作用. 这一发现影响了我们对排水功能的理解.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 在AcrAB-TolC排泄赋予Escherichia大肠杆菌的多药性耐药性.
- AcrB是负责基质结合和能量转导的核心输送器.
- F610A突变显著降低了各种基质的最小抑制度,包括多克索鲁比辛.
研究的目的:
- 通过计算评估F610A突变对AcrB传送器功能的影响.
- 调查F610A突变影响多克索鲁素运输的机制.
主要方法:
- 计算机建模和模拟技术.
- 对基质 - 载体相互作用和形状变化的分析.
- 多克索鲁比被用作模型基质.
主要成果:
- F610A突变导致多克索鲁比辛在AcrB结合口袋中结合得更深,从而增加相互作用强度.
- 在突变后,多克索鲁比要么被保留在结合部位,要么被挤出非功能方向.
- 这表明运输受损,而不是仅仅减少结合亲和力.
结论:
- 微妙的氨基酸变化,如F610A,可以深刻地改变多药物转运器的功能.
- 药物耐药性降低的机制与挤出受损有关,而不仅仅是改变结合.
- 这项研究提供了关于排泄与基板相互作用的复杂动态的见解.
相关概念视频
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:
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...
The Significance of Membrane Transport
The transport of solutes across the cell membrane is essential for metabolic processes, like maintaining cell size and volume, generating the action potential, exchanging nutrients and gases, etc. Membrane transport can be either passive or active. It can be simple diffusion, facilitated, or mediated transport aided by transport proteins such as transporters and channels.
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
Membrane Asymmetry Regulating Transporters
Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...


