Sauna Zuben E, Ambudkar Suresh V
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 2120, 37 Convent Drive, Bethesda, MD 20892-4256, USA.
Mol Cancer Ther. 2007 Jan;6(1):13-23. doi: 10.1158/1535-7163.MCT-06-0155.
The efflux of drugs by the multidrug transporter P-glycoprotein (Pgp; ABCB1) is one of the principal means by which cancer cells evade chemotherapy and exhibit multidrug resistance. Mechanistic studies of Pgp-mediated transport, however, transcend the importance of this protein per se as they help us understand the transport pathway of the ATP-binding cassette proteins in general. The ATP-binding cassette proteins comprise one of the largest protein families, are central to cellular physiology, and constitute important drug targets. The functional unit of Pgp consists of two nucleotide-binding domains (NBD) and two transmembrane domains that are involved in the transport of drug substrates. Early studies postulated that conformational changes as a result of ATP hydrolysis were transmitted to the transmembrane domains bringing about drug transport. More recent structural and biochemical studies on the other hand suggested that ATP binds at the interface of the two NBDs and induces the formation of a closed dimer, and it has been hypothesized that this dimerization and subsequent ATP hydrolysis powers transport. Based on the mutational and biochemical work on Pgp and structural studies with isolated NBDs, we review proposed schemes for the catalytic cycle of ATP hydrolysis and the transport pathway.
多药转运蛋白P-糖蛋白（Pgp；ABCB1）介导的药物外排是癌细胞逃避化疗并表现出多药耐药性的主要方式之一。然而，Pgp介导转运的机制研究，其重要性超越了该蛋白本身，因为它们有助于我们总体上理解ATP结合盒蛋白的转运途径。ATP结合盒蛋白是最大的蛋白家族之一，对细胞生理学至关重要，并且构成重要的药物靶点。Pgp的功能单元由两个核苷酸结合结构域（NBD）和两个参与药物底物转运的跨膜结构域组成。早期研究推测，ATP水解导致的构象变化会传递到跨膜结构域，从而实现药物转运。另一方面，最近的结构和生化研究表明，ATP结合在两个NBD的界面处并诱导形成封闭的二聚体，并且有人推测这种二聚化以及随后的ATP水解为转运提供动力。基于对Pgp的突变和生化研究以及对分离的NBD的结构研究，我们综述了ATP水解催化循环和转运途径的提出方案。
