The structural basis of promiscuity in small multidrug resistance transporters

Ali A. Kermani, Christian B. Macdonald, Olive E. Burata, B. Koff, Akiko Koide, Eric Denbaum, Shohei Koide and Randy B. Stockbridge ()
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Ali A. Kermani: University of Michigan
Christian B. Macdonald: University of Michigan
Olive E. Burata: University of Michigan
B. Koff: University of Michigan
Akiko Koide: New York University Langone Medical Center
Eric Denbaum: New York University Langone Medical Center
Shohei Koide: New York University Langone Medical Center
Randy B. Stockbridge: University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract By providing broad resistance to environmental biocides, transporters from the small multidrug resistance (SMR) family drive the spread of multidrug resistance cassettes among bacterial populations. A fundamental understanding of substrate selectivity by SMR transporters is needed to identify the types of selective pressures that contribute to this process. Using solid-supported membrane electrophysiology, we find that promiscuous transport of hydrophobic substituted cations is a general feature of SMR transporters. To understand the molecular basis for promiscuity, we solved X-ray crystal structures of a SMR transporter Gdx-Clo in complex with substrates to a maximum resolution of 2.3 Å. These structures confirm the family’s extremely rare dual topology architecture and reveal a cleft between two helices that provides accommodation in the membrane for the hydrophobic substituents of transported drug-like cations.

Date: 2020
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DOI: 10.1038/s41467-020-19820-8

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