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

我们将研究来自选定的革兰氏阴性菌的三抗结瘤细胞分裂（RND）型药物外排复合物的混杂底物结合、分子设置和运输活性的结构决定因素。在CRC 807的框架下，我们的目标是通过（高分辨率）单粒子冷冻电镜、固态核磁共振、EPR和x射线晶体学，研究同源RND成分的多种药物结合表型的分子基础，以及来自其他革兰氏阴性细菌的三方组装的分子结构。体外形成的三方组件将使我们能够表征重建系统中的药物运输，使用具有改变药物结合特异性的RND外排泵变体将使我们能够详细分析混杂药物结合的分子基础。本研究的综合结果将为rnd型三方多药外排复合物的结构-功能关系提供详细的见解。

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.