Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Monday Speaker Abstracts

STRUCTURAL BASIS OF DRUG BINDING TO MULTIDRUG TRANSPORTERS REVEALED BY CRYO-ELECTRON MICROSCOPY Kaspar Locher 1 ; 1 ETH Zurich, Institute of Molecular Biology and Biophysics, Zurich, Switzerland Multidrug transporters recognise and extrude toxic compounds from cells. The accepted substrates are generally hydrophobic but also include compounds that contain charged groups. To understand the interaction of drugs with these transporters, high resolution structural insight is required. In the past, X-ray crystallography was primarily used to determine structures of multidrug transporters. Unfortunately, the high detergent concentrations during crystallisation experiments often prevented the visualisation of bound drugs, in particular because the affinity of the substrates to the transporters are not high. Using single particle cryo-electron microscopy, we have determined several structures of bacterial and eukaryotic multidrug transporters. Because the studies were performed using nanodisc-reconstituted rather than detergent-solubilised protein, we could visualise bound drugs. For multidrug ABC transporters, we found that a single substrate molecule is generally bound at a central binding pocket. In contrast, several inhibitors bound in pairs. These studies provide key insight to understand the broad specificity of multidrug transporters, which may provide avenues to explore novel antibiotic approaches.

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