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

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.

Authors:
 [1]; ORCiD logo [1];  [1];  [1];  [2];  [2]; ORCiD logo [2]; ORCiD logo [1]
  1. Univ. of Michigan, Ann Arbor, MI (United States)
  2. New York Univ. School of Medicine, New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1729716
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kermani, Ali A., Macdonald, Christian B., Burata, Olive E., Ben Koff, B., Koide, Akiko, Denbaum, Eric, Koide, Shohei, and Stockbridge, Randy B.. The structural basis of promiscuity in small multidrug resistance transporters. United States: N. p., 2020. Web. https://doi.org/10.1038/s41467-020-19820-8.
Kermani, Ali A., Macdonald, Christian B., Burata, Olive E., Ben Koff, B., Koide, Akiko, Denbaum, Eric, Koide, Shohei, & Stockbridge, Randy B.. The structural basis of promiscuity in small multidrug resistance transporters. United States. https://doi.org/10.1038/s41467-020-19820-8
Kermani, Ali A., Macdonald, Christian B., Burata, Olive E., Ben Koff, B., Koide, Akiko, Denbaum, Eric, Koide, Shohei, and Stockbridge, Randy B.. Fri . "The structural basis of promiscuity in small multidrug resistance transporters". United States. https://doi.org/10.1038/s41467-020-19820-8. https://www.osti.gov/servlets/purl/1729716.
@article{osti_1729716,
title = {The structural basis of promiscuity in small multidrug resistance transporters},
author = {Kermani, Ali A. and Macdonald, Christian B. and Burata, Olive E. and Ben Koff, B. and Koide, Akiko and Denbaum, Eric and Koide, Shohei and Stockbridge, Randy B.},
abstractNote = {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.},
doi = {10.1038/s41467-020-19820-8},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {11}
}

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