多重耐药性相关蛋白2的运输和调节机制的结构基础
Eriko Koide1, Harlan L Pietz1,2, Jean Beltran3
1Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY, USA.
Nature communications
|January 8, 2025
概括
多种药物耐药性相关蛋白2 (MRP2) 是一种由ATP驱动的载体,对肝脏健康和化疗耐药性至关重要. Cryo-EM揭示了其监管领域控制基质访问,作为药物运输的选择性测量仪.
科学领域:
- 生物化学 生化学
- 结构生物学 结构生物学
- 分子运输分子的运输.
背景情况:
- 多重耐药性相关蛋白2 (MRP2) 是一种依赖ATP的转运体,对肝脏平衡至关重要.
- MRP2在细胞防御机制中起着重要作用,并与化疗耐药性有关.
研究的目的:
- 阐明人类MRP2功能背后的结构机制.
- 了解MRP2如何与基质和ATP相互作用以调节运输.
- 提供与MRP2.2相关的多药耐药性结构基础的见解.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定人类MRP2.2的高分辨率结构.
- 结构在三个不同的功能状态中得到解决:自抑制,基质结合前转移和ATP结合后转移.
- 对与各种基板结合的MRP2进行了比较结构分析.
主要成果:
- 自抑制状态的特点是细胞质调节 (R) 域阻断基质结合部位,并形成ATP结合部位的一部分.
- 基质结合会诱导R域的位移,从而启动传输所需的形状变化.
- R域充当选择性测量器,需要足够的基质度来启动运输.
- 结构分析揭示了MRP2如何识别各种基质,这有助于其在多药性耐药性方面的作用.
结论:
- R域对于调节MRP2活性和基质选择性至关重要.
- 了解MRP2的构造状态为其在药物运输和耐药性方面的作用提供了机制基础.
- 这些发现为治疗环境中调节MRP2活性提供了潜在的目标.
相关概念视频
01:06Carrier-Mediated Transport
247
Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
247
01:31ABC Transporters: Exporter
4.1K
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...
4.1K
01:31Membrane Transporters
10.3K
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...
10.3K
01:24Cellular Membranes and Drug Transport
276
Drugs must traverse multiple biological barriers, such as multi-layered skin, single-layered intestinal epithelium, and the plasma membrane, to reach their target sites within the body. The plasma membrane, a highly structured composite of phospholipids, carbohydrates, and proteins, is the cell's protective boundary, facilitating selective substance exchange.
Phospholipids arrange themselves into a bilayer, with hydrophilic heads oriented outward and hydrophobic tails facing inward.
Phospholipids arrange themselves into a bilayer, with hydrophilic heads oriented outward and hydrophobic tails facing inward.
276
01:19Drug Absorption Mechanism: Carrier-Mediated Membrane Transport
3.5K
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...
3.5K
01:27ABC Transporters: Importer
2.7K
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:
2.7K