Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1.
Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1.
复制标题
DOI：
10.1016/j.tibs.2009.07.009
复制
发表时间：
2010-01
影响因子：
13.8
通讯作者：
van Veen HW
中科院分区：
文献类型：
--
作者：
Gutmann DA;Ward A;Urbatsch IL;Chang G;van Veen HW
多药ABC转运体可以从细胞内运输多种药物。对哺乳动物多药耐药原型--三磷酸腺苷结合盒转运体P-糖蛋白(ABCB1)的研究揭示了许多有趣的功能和生化特征。然而，关于它对结构无关的配体具有广泛的特异性的分子基础，我们的认识仍然存在差距。最近，无配体和配体结合的ABCB1的第一个晶体结构显示其两个膜结构域之间的空腔中有配体结合，现在可以从结构的角度解释先前对多特异性的观察。新的ABCB1晶体结构还表明，跨膜螺旋的轴向旋转对于跨膜转运过程中配体的高亲和力结合和低亲和力释放具有关键作用。
Multidrug ABC transporters can transport a wide range of drugs from the cell. Ongoing studies of the prototype mammalian multidrug resistance ATP-binding cassette transporter P-glycoprotein (ABCB1) have revealed many intriguing functional and biochemical features. However, a gap remains in our knowledge regarding the molecular basis of its broad specificity for structurally unrelated ligands. Recently, the first crystal structures of ligand-free and ligand-bound ABCB1 showed ligand binding in a cavity between its two membrane domains, and now previous observations on polyspecificity can be interpreted in a structural context. The new ABCB1 crystal structures also suggest a critical role for an axial rotation of transmembrane helices for high-affinity binding and low-affinity release of ligands during transmembrane transport.