人类药物载体OATP1B1和OATP1B3的结构
Anca-Denise Ciută1, Kamil Nosol1, Julia Kowal1
1Institute of Molecular Biology and Biophysics, Department of Biology, ETH Zürich, Zürich, Switzerland.
Nature communications
|September 18, 2023
概括
这项研究揭示了有机离子载体多 (OATPs) 1B1和1B3.3的冷-EM结构. 这些结构为药物运输机制和潜在的药物相互作用提供了洞察力.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 有机阴离子载体多 (OATPs),特别是OATP1B1和OATP1B3,是肝脏药物吸收和排出的关键膜蛋白.
- 在OATPs中的多态性可以导致药物清除的减少,药物不良反应 (例如,他类药物诱导的狂体痛解) 和药物相互作用.
- 尽管OATPs具有临床意义,但它们的结构基础和传输机制仍然在很大程度上是未知的.
研究的目的:
- 使用冷电子显微镜 (cryo-EM) 确定人类OATP1B1和OATP1B3的高分辨率结构.
- 阐明这些关键药物载体的基质结合和运输机制的结构基础.
- 为了解OATP功能,遗传变异和药物相互作用提供结构基础.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 解析了人类OATP1B1和OATP1B3.3的结构.
- 在存在合成Fab碎片和功能上不同的状态下确定结构.
- 计算方法,包括in silico对接,用于分析基质结合和相互作用.
主要成果:
- OATP1B1的冷-EM结构揭示了在一个口袋中结合的雌激素-3-硫酸盐分子,这解释了它对有机离子的偏好,并使其能够在类药物中进行合.
- 在无药物状态下确定的OATP1B3的结构显示,在一个保存的动机和一个关键的胺基残留物处有结合的二碳酸盐分子.
- 这些发现为OATP的不同功能状态和基质识别提供了结构性的见解.
结论:
- OATP1B1和OATP1B3的确定的结构为它们的架构和功能提供了前所未有的原子级细节.
- 这些发现合理化了基质特异性,并为了解OATP变体和药物相互作用的发生提供了基础.
- 这些结构性见解对于推动药物开发,预测药物动力学变异性和减轻药物不良事件至关重要.
相关概念视频
Carrier-Mediated Transport
466
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...
466
ABC Transporters: Exporter
4.4K
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...
4.4K
Membrane Transporters
11.5K
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...
11.5K
The Significance of Membrane Transport
27.6K
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...
27.6K
Facilitated Diffusion
505
The plasma membrane, a critical structure in cellular biology, houses an array of transporters, or carrier proteins, interspersed within its lipid bilayer. These proteins play a crucial role in solute transport through facilitated diffusion, a form of passive diffusion that uses transporters to move the molecules across the membrane.
In this process, substrates such as organic compounds and ions interact with a transporter on one side, triggering conformational changes in proteins that enable...
In this process, substrates such as organic compounds and ions interact with a transporter on one side, triggering conformational changes in proteins that enable...
505
ABC Transporters: Importer
2.8K
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:
2.8K


