P-糖蛋白结构及作用机制

Molecular Structure and Functions of P-glycoprotein

ABC(ATP-binding cassette)转运蛋白广泛存在于各种生物体细胞中,例如细菌的内层细胞浆膜和真核生物的细胞膜和细胞器膜.其利用与ATP的结合和水解供能进行底物的跨膜转运,其中一部分ABC转运蛋白能转运多种疏水性分子.P-糖蛋白隶属于ABC转运蛋白超家族,是研究最为透彻的一员,主要功能是防止机体对外来有害物质的摄入.P-糖蛋白(P-glycoprotein)由4个基本结构域组成,2个跨膜区和2个位于细胞浆内的核苷酸结合区.核苷酸结合区参与ATP的结合和水解,而各由6个α跨膜螺旋组成的2个跨膜区联合构成了底物跨膜转运的通道.P-糖蛋白能转运多种不同结构的底物,包括脂类、胆汁酸、多肽和外源性化学物质,这对机体的生存至关重要,但同时也存在不利的一面,包括干扰了药物的运输,从而导致了多药耐药现象的产生.本文就P-糖蛋白的分子结构和作用机制的最新研究进展进行综述.

P-glycoprotein （P-gp） is a well-characterized member of the super-family of ABC （ATP-binding cassette） transporters that are present in the cells of all organisms, either on the cytoplasmic （inner） membranes of bacteria, or on both the plasma membrane and organelle membranes of eukaryotes. The basic functional unit of P-gp consists of four domains. Two cytoplasmic nucleotide-binding domains （NBDs） that bind and hydrolyze ATP, plus two transmembrane domains （TMDs） that each consists of six membrane- spanning α-helices to form a substrate membrane-crossing pathway, where the energy from ATP hydrolysis is used to transport substrates across cell membranes. Some ABC transporters have evolved with various specificities for transporting hydrophobic molecules. One major function of these proteins is to limit the uptake of the toxic compounds from the outside into the body. P-gp transports a wide range of compounds, including lipids, bile acids, xenobiotics and peptides, that is advantageous, but its interfere with the delivery of drugs can be disadvantageous for certain target tissues and result in multidrug resistance. In the present review, we will provide the latest advances in the studies of the molecular structure basis and the mechanism of P- glycoprotein functions.