Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.
Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.
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DOI：
10.1126/science.1168750
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发表时间：
2009-03-27
期刊：
影响因子：
--
通讯作者：
Chang G
中科院分区：
文献类型：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
P-糖蛋白（Pgp）通过输出数百种化学上不相关的毒素来解毒细胞，但在癌症治疗中与多药耐药性有关。底物混杂性是Pgp活性的标志，因此多特异性药物结合的结构描述对于合理设计抗癌药物和MDR抑制剂是重要的。apo-Pgp在3.8 nm处的X射线结构显示出一个6,000 nm 3的内腔，两个核苷酸结合结构域（NBD）间隔30 nm。两个额外的Pgp结构与环肽抑制剂证明不同的药物结合位点的内部空腔能够立体选择性的基础上，疏水和芳香族相互作用。载脂蛋白和药物结合的Pgp结构具有通向细胞质和脂质双层的内小叶的门户，用于药物进入。面向内的构象代表了转运循环的初始阶段，其能够与药物结合。
P-glycoprotein (Pgp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance in the treatment of cancers. Substrate promiscuity is a hallmark of Pgp activity, thus a structural description of polyspecific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo-Pgp at 3.8 Å reveals an internal cavity of ∼6,000 Å3 with a 30 Å separation of the two nucleotide binding domains (NBD). Two additional Pgp structures with cyclic peptide inhibitors demonstrate distinct drug binding sites in the internal cavity capable of stereo-selectivity that is based on hydrophobic and aromatic interactions. Apo- and drug-bound Pgp 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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