The structural basis of promiscuity in small multidrug resistance transporters

Kermani, Ali A.; Macdonald, Christian B.; Burata, Olive E.; Ben Koff, B.; Koide, Akiko; Denbaum, Eric; Koide, Shohei; Stockbridge, Randy B.

doi:10.1038/s41467-020-19820-8

Title: The structural basis of promiscuity in small multidrug resistance transporters

Journal Article · 26 November 2020 · Nature Communications

DOI: https://doi.org/10.1038/s41467-020-19820-8 · OSTI ID:1729716

Kermani, Ali A. ^[1];

^[1]; Burata, Olive E. ^[1]; Ben Koff, B. ^[1]; Koide, Akiko ^[2]; Denbaum, Eric ^[2];

^[2];

^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
New York Univ. School of Medicine, New York, NY (United States)

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.

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Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: NIH; USDOE

OSTI ID:: 1729716

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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