Struktur-Funktions-Beziehung von dreiteiligen Arzneimittel-auswärtspumpenden RND-Komplexen s (P18)

我们将研究来自选定革兰氏阴性细菌的三重耐药结节细胞分裂（RND）型药物外排复合物的混杂底物结合、分子设置和转运活性的结构决定因素。在CRC 807的框架中，我们的目标是通过使用（高分辨率）单粒子冷冻EM，固态NMR，EPR和X射线晶体学来检查同源RND组分的多种药物结合表型的分子基础和来自其他革兰氏阴性细菌的三方组装的分子设置。在体外形成的三方组件将使我们能够表征药物转运在一个重建的系统和使用RND外排泵的变体与改变药物结合特异性将使详细的分析混杂的药物结合的分子基础。从拟议的研究的综合结果将提供详细的了解RND型三方多药物外排复合物的结构-功能关系。

We will investigate the structural determinants for the promiscuous substrate binding, molecular setup, and transport activity of tripartite Resistance Nodulation cell Division (RND)-type drug efflux complexes from selected Gram-negative bacteria. In the framework of the CRC 807, we aim to examine the molecular basis of multiple drug-binding phenotypes of homologue RND components and the molecular setup of tripartite assemblies from other Gram-negative bacteria by using (high-resolution) single-particle cryo-EM, solid-state NMR, EPR, and X-ray crystallography. The in vitro formation of tripartite assemblies will allow us to characterize drug transport in a reconstituted system and the use of RND efflux pump variants with altered drug binding specificity will enable the detailed analysis on the molecular basis of promiscuous drug binding. The combined results from the proposed research will provide detailed insight into the structure-function relationship of RND-type tripartite multidrug efflux complexes.