Electrostatic lock in the transport cycle of the multidrug resistance transporter EmrE

Proceedings of the National Academy of Sciences of the United States of America
Josh V VermaasEmad Tajkhorshid

Abstract

EmrE is a small, homodimeric membrane transporter that exploits the established electrochemical proton gradient across the Escherichia coli inner membrane to export toxic polyaromatic cations, prototypical of the wider small-multidrug resistance transporter family. While prior studies have established many fundamental aspects of the specificity and rate of substrate transport in EmrE, low resolution of available structures has hampered identification of the transport coupling mechanism. Here we present a complete, refined atomic structure of EmrE optimized against available cryo-electron microscopy (cryo-EM) data to delineate the critical interactions by which EmrE regulates its conformation during the transport process. With the model, we conduct molecular dynamics simulations of the transporter in explicit membranes to probe EmrE dynamics under different substrate loading and conformational states, representing different intermediates in the transport cycle. The refined model is stable under extended simulation. The water dynamics in simulation indicate that the hydrogen-bonding networks around a pair of solvent-exposed glutamate residues (E14) depend on the loading state of EmrE. One specific hydrogen bond from a tyrosine (Y...Continue Reading

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Citations

Oct 6, 2018·The Journal of Biological Chemistry·Nathan E ThomasKatherine A Henzler-Wildman
Apr 17, 2020·Biotechnology Journal·Ying ZhuChun Li
Jul 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jani Reddy BollaCarol V Robinson
Aug 1, 2018·Proceedings of the National Academy of Sciences of the United States of America·Jana Shen
Nov 29, 2020·Nature Communications·Ali A KermaniRandy B Stockbridge
Jan 10, 2021·Nature Communications·Alexander A ShcherbakovMei Hong
Jun 4, 2019·Journal of Molecular Biology·Chao WuKatherine A Henzler-Wildman
Dec 10, 2019·Trends in Biochemical Sciences·Tao JiangEmad Tajkhorshid
Jun 3, 2021·Antibiotics·Manuel F VarelaSanath H Kumar
Oct 20, 2018·The Journal of Physical Chemistry. B·Piao MaSusan B Rempe
Oct 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Jianping LiNathaniel J Traaseth
Oct 7, 2021·PLoS Computational Biology·Jakub JuraszMiłosz Wieczór
Dec 4, 2021·Frontiers in Bioengineering and Biotechnology·Sen LiuWei Ye

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Methods Mentioned

BETA
NMR
X-ray
electron paramagnetic resonance

Software Mentioned

EmrE
PROCHECK
GROMACS
NumPy
SciPy
psfgen
CHARMM
TeXshade
CHARMM36
NAMD

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