Ramaswamy Venkata K, Vargiu Attilio V, Malloci Giuliano, Dreier Jürg, Ruggerone Paolo
Department of Physics, University of Cagliari, Monserrato, Italy.
Basilea Pharmaceutica International Ltd., Basel, Switzerland.
Front Microbiol. 2018 Jun 1;9:1144. doi: 10.3389/fmicb.2018.01144. eCollection 2018.
Secondary multidrug transporters of the resistance-nodulation-cell division (RND) superfamily contribute crucially to antibiotic resistance in Gram-negative bacteria. Compared to the most studied transporter AcrB of , little is known about the molecular determinants of distinct polyspecificities of the most important RND transporters MexB and MexY of . In an effort to add knowledge on this topic, we performed an exhaustive atomic-level comparison of the main putative recognition sites (access and deep binding pockets) in these two Mex transporters. We identified an underlying link between some structural, chemical and dynamical features of the binding pockets and the physicochemical nature of the corresponding substrates recognized by either one or both pumps. In particular, mosaic-like lipophilic and electrostatic surfaces of the binding pockets provide for both proteins several multifunctional sites for diffuse binding of diverse substrates. Specific lipophilicity signatures of the weakly conserved deep pocket suggest a key role of this site as a selectivity filter as in Acr transporters. Finally, the different dynamics of the bottom-loop in MexB and MexY support its possible role in binding of large substrates. Our work represents the first comparative study of the major RND transporters in and also the first structure-based study of MexY, for which no experimental structure is available yet.
抗药-固氮-细胞分裂（RND）超家族的次级多药转运蛋白对革兰氏阴性菌的抗生素耐药性起着至关重要的作用。与研究最多的转运蛋白AcrB相比，人们对最重要的RND转运蛋白MexB和MexY的不同多特异性的分子决定因素知之甚少。为了增加关于这个主题的知识，我们对这两种Mex转运蛋白中的主要假定识别位点（入口和深度结合口袋）进行了详尽的原子水平比较。我们确定了结合口袋的一些结构、化学和动力学特征与任一或两者泵所识别的相应底物的物理化学性质之间的潜在联系。特别是，结合口袋的镶嵌样亲脂性和静电表面为两种蛋白质提供了几个用于不同底物扩散结合的多功能位点。弱保守深度口袋的特定亲脂性特征表明该位点作为选择性过滤器，与Acr转运蛋白中的作用相同。最后，MexB和MexY中底部环的不同动力学支持其在大底物结合中的可能作用。我们的工作代表了对[具体物种]中主要RND转运蛋白的首次比较研究，也是对MexY的首次基于结构的研究，目前尚无其实验结构。
