Molecular mechanism of substrate recognition and transport by P-glycoprotein

P-糖蛋白底物识别和转运的分子机制

基本信息

批准号：
17570113
负责人：
OMOTE Hiroshi
金额：
$ 2.24万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17570113/
关键词：
P-glycoprotein multidrug resistance substrate recognition P-糖タンパク質薬物輸送 MATE 疎水性物質

项目摘要

Broad substrate specificity of human P-glycoprotein (ABCB1) is an essential feature of multidrug resistance. Transport substrates of P-glycoprotein are mostly hydrophobic and many of them have net positive charge. These compounds partition into the membrane. Utilizing the energy of ATP hydrolysis, P-glycoprotein is thought to take up substrates from the cytoplasmic leaflet of the plasma membrane and to transport themto the outside of the cell. We examined this model by molecular dynamics simulation of the lipid bilayer, in the presence of transport substrates together with an atomic resolution structural model of P-glycoprotein. Taken together with previous electron paramagnetic resonance studies, the results suggest that most transported drugs are concentrated near the surface zone of the inner leaflet of the plasma membrane. Here the drugs can easily diffuse laterally into the drug-binding site of P-glycoprotein through an open cleft. It was concluded that the initial high-affinity drugbinding site was located in the interfacial surface area of P-glycoprotein in contact with the membrane interface. Based on these results and our recent kinetic studies, a "solvation exchange" drug transport mechanism of P-glycoprotein is discussed. A molecular basis for the improved colchicine transport efficiency by the much-studied colchicine-resistance G185V mutant human P-glycoprotein is also provided.

人P-糖蛋白（ABCB1）的宽底物特异性是多药耐药性的重要特征。 P-糖蛋白的转运底物主要是疏水性，其中许多具有净阳性电荷。这些化合物分配到膜中。利用ATP水解的能量，人们认为P-糖蛋白从质膜的细胞质叶片中吸收底物，并将其运输到细胞外部。我们通过脂质双层的分子动力学仿真检查了该模型，并在运输底物的存在下以及P-糖蛋白的原子分辨率结构模型。与先前的电子顺磁共振研究一起，结果表明，大多数运输的药物都集中在质膜内部小叶的表面区域附近。在这里，药物很容易通过开放的裂口横向扩散到P-糖蛋白的药物结合部位。得出的结论是，最初的高亲和力药物结合位点位于与膜界面接触的P-糖蛋白的界面表面积。基于这些结果和我们最近的动力学研究，讨论了P-糖蛋白的“溶剂化交换”药物转运机制。还提供了备受研究的秋水仙碱G185V突变体人类P-糖蛋白提高秋水仙碱转运效率的分子基础。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interaction of transported drugs with the lipid bilayer and P-glyc oprotein through a solvation exchange mechanism.

运输的药物通过溶剂化交换机制与脂质双层和 P-糖蛋白相互作用。

DOI：
发表时间：
2006
期刊：
Biophysical Journal (印刷中)
影响因子：
0
作者：
Juge;N.;Omote H.;Juge N.;Omote H
通讯作者：
Omote H

Interaction of transported drugs with the lipid bilayer and P-glycoprotein through a solvation exchange mechanism.

运输的药物通过溶剂化交换机制与脂质双层和 P-糖蛋白相互作用。

DOI：
发表时间：
2006
期刊：
Biophysical J. 90
影响因子：
0
作者：
Aki Kitai;Maiko Koga;Akikazu Murakami;Takachika Azuma;Masayuki Oda;Maiko Koga;北井麻希;Hiroshi Omote
通讯作者：
Hiroshi Omote

Vesicular glutamate transporter contains two independent transport machineries