The structural basis of promiscuity in small multidrug resistance transporters

Nat Commun. 2020 Nov 27;11(1):6064. doi: 10.1038/s41467-020-19820-8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Biological Transport
  • Crystallography, X-Ray
  • Drug Resistance, Multiple, Bacterial*
  • Escherichia coli / metabolism
  • Gene Transfer, Horizontal
  • Guanine / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Riboswitch
  • Substrate Specificity


  • Bacterial Proteins
  • Membrane Transport Proteins
  • Riboswitch
  • Guanine