Zheleznova E E, Markham P N, Neyfakh A A, Brennan R G
Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland 97201-3098, USA.
Cell. 1999 Feb 5;96(3):353-62. doi: 10.1016/s0092-8674(00)80548-6.
Multidrug-efflux transporters demonstrate an unusual ability to recognize multiple structurally dissimilar toxins. A comparable ability to bind diverse hydrophobic cationic drugs is characteristic of the Bacillus subtilis transcription regulator BmrR, which upon drug binding activates expression of the multidrug transporter Bmr. Crystal structures of the multidrug-binding domain of BmrR (2.7 A resolution) and of its complex with the drug tetraphenylphosphonium (2.8 A resolution) revealed a drug-induced unfolding and relocation of an alpha helix, which exposes an internal drug-binding pocket. Tetraphenylphosphonium binding is mediated by stacking and van der Waals contacts with multiple hydrophobic residues of the pocket and by an electrostatic interaction between the positively charged drug and a buried glutamate residue, which is the key to cation selectivity. Similar binding principles may be used by other multidrug-binding proteins.
多药外排转运蛋白表现出一种不同寻常的能力，能够识别多种结构不同的毒素。枯草芽孢杆菌转录调节因子BmrR具有类似的结合多种疏水性阳离子药物的能力，该调节因子在药物结合后会激活多药转运蛋白Bmr的表达。BmrR多药结合结构域的晶体结构（分辨率为2.7埃）及其与药物四苯基鏻的复合物的晶体结构（分辨率为2.8埃）显示，药物诱导了一个α螺旋的展开和重新定位，从而暴露出一个内部药物结合口袋。四苯基鏻的结合是通过与口袋中多个疏水残基的堆积和范德华相互作用以及带正电荷的药物与一个埋藏的谷氨酸残基之间的静电相互作用介导的，这是阳离子选择性的关键。其他多药结合蛋白可能也采用类似的结合原理。
