Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding

被引:1568
作者
Aller, Stephen G. [1 ]
Yu, Jodie [1 ]
Ward, Andrew [2 ]
Weng, Yue [1 ,4 ]
Chittaboina, Srinivas [1 ]
Zhuo, Rupeng [3 ]
Harrell, Patina M. [3 ]
Trinh, Yenphuong T. [3 ]
Zhang, Qinghai [1 ]
Urbatsch, Ina L. [3 ]
Chang, Geoffrey [1 ]
机构
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA
[3] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA
[4] Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China
关键词
ABC TRANSPORTER; MULTIDRUG-RESISTANCE; CASSETTE TRANSPORTER; NUCLEOTIDE-BINDING; CRYSTAL-STRUCTURE; PURIFICATION; CONFORMATION; RECOGNITION; MECHANISMS; MICROSCOPY;
D O I
10.1126/science.1168750
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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 similar to 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.
引用
收藏
页码:1718 / 1722
页数:5
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