多重耐药
化学
药品
P-糖蛋白
细胞质
脂质双层
结合位点
合理设计
血浆蛋白结合
埃
糖蛋白
立体化学
药物设计
肽
生物化学
生物物理学
生物
结晶学
药理学
膜
遗传学
抗生素
作者
Stephen G. Aller,Jodie Yu,Andrew B. Ward,Yue Weng,Srinivas Chittaboina,Rupeng Zhuo,Patina M. Harrell,Yenphuong T. Trinh,Qinghai Zhang,Ina L. Urbatsch,Geoffrey Chang
出处
期刊:Science
[American Association for the Advancement of Science]
日期:2009-03-27
卷期号:323 (5922): 1718-1722
被引量:1677
标识
DOI:10.1126/science.1168750
摘要
P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of ∼6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.
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