X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release
Abstract
Neurotransmitter:sodium symporters (NSS) are conserved from bacteria to man and serve as targets for drugs, including antidepressants and psychostimulants. Here we report the X-ray structure of the prokaryotic NSS member, LeuT, in a Na+/substrate-bound, inward-facing occluded conformation. To obtain this structure, we were guided by findings from single-molecule fluorescence spectroscopy and molecular dynamics simulations indicating that L-Phe binding and mutation of the conserved N-terminal Trp8 to Ala both promote an inward-facing state. Compared to the outward-facing occluded conformation, our structure reveals a major tilting of the cytoplasmic end of transmembrane segment (TM) 5, which, together with release of the N-terminus but without coupled movement of TM1, opens a wide cavity towards the second Na+ binding site. The structure of this key intermediate in the LeuT transport cycle, in the context of other NSS structures, leads to the proposal of an intracellular release mechanism of substrate and ions in NSS proteins.
- Authors:
-
[1];
[2];
[4];
[7];
[7];
[9];
[8];
[3];
[11];
[3]
- Univ. of Copenhagen (Denmark). Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences; Univ. of Copenhagen (Denmark). Membrane Protein Structural Biology Group, Department of Biomedical Sciences, Faculty of Health and Medical Sciences
- Aarhus Univ. (Denmark). DANDRITE - Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics; Aarhus Univ. (Denmark). Interdisciplinary Nanoscience Center iNANO
- Univ. of Copenhagen (Denmark). Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences
- Cornell Univ. New York, NY (United States). Dept. of Physiology and Biophysics, Weill Cornell Medical College
- Columbia Univ., Vagelos College of Physicians & Surgeon and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY (United States). Dept. of Psychiatry
- St. Jude Children’s Research Hospital, Memphis, TN (United States). Dept. of Structural Biology
- Univ. of Copenhagen (Denmark). Membrane Protein Structural Biology Group, Department of Biomedical Sciences, Faculty of Health and Medical Sciences
- Cornell Univ. New York, NY (United States). Dept. of Physiology and Biophysics, Weill Cornell Medical College
- St. Jude Children’s Research Hospital, Memphis, TN (United States). Dept. of Structural Biology
- Columbia Univ., Vagelos College of Physicians & Surgeon and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY (United States). Dept. of Psychiatry
- Aarhus Univ. (Denmark). DANDRITE - Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics; Aarhus Univ. (Denmark). Interdisciplinary Nanoscience Center iNANO
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1624251
- Grant/Contract Number:
- AC02-05CH11231; AC05-00OR22725
- 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:
- Science & Technology - Other Topics
Citation Formats
Gotfryd, Kamil, Boesen, Thomas, Mortensen, Jonas S., Khelashvili, George, Quick, Matthias, Terry, Daniel S., Missel, Julie W., LeVine, Michael V., Gourdon, Pontus, Blanchard, Scott C., Javitch, Jonathan A., Weinstein, Harel, Loland, Claus J., Nissen, Poul, and Gether, Ulrik. X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. United States: N. p., 2020.
Web. doi:10.1038/s41467-020-14735-w.
Gotfryd, Kamil, Boesen, Thomas, Mortensen, Jonas S., Khelashvili, George, Quick, Matthias, Terry, Daniel S., Missel, Julie W., LeVine, Michael V., Gourdon, Pontus, Blanchard, Scott C., Javitch, Jonathan A., Weinstein, Harel, Loland, Claus J., Nissen, Poul, & Gether, Ulrik. X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. United States. https://doi.org/10.1038/s41467-020-14735-w
Gotfryd, Kamil, Boesen, Thomas, Mortensen, Jonas S., Khelashvili, George, Quick, Matthias, Terry, Daniel S., Missel, Julie W., LeVine, Michael V., Gourdon, Pontus, Blanchard, Scott C., Javitch, Jonathan A., Weinstein, Harel, Loland, Claus J., Nissen, Poul, and Gether, Ulrik. Fri .
"X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release". United States. https://doi.org/10.1038/s41467-020-14735-w. https://www.osti.gov/servlets/purl/1624251.
@article{osti_1624251,
title = {X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release},
author = {Gotfryd, Kamil and Boesen, Thomas and Mortensen, Jonas S. and Khelashvili, George and Quick, Matthias and Terry, Daniel S. and Missel, Julie W. and LeVine, Michael V. and Gourdon, Pontus and Blanchard, Scott C. and Javitch, Jonathan A. and Weinstein, Harel and Loland, Claus J. and Nissen, Poul and Gether, Ulrik},
abstractNote = {Neurotransmitter:sodium symporters (NSS) are conserved from bacteria to man and serve as targets for drugs, including antidepressants and psychostimulants. Here we report the X-ray structure of the prokaryotic NSS member, LeuT, in a Na+/substrate-bound, inward-facing occluded conformation. To obtain this structure, we were guided by findings from single-molecule fluorescence spectroscopy and molecular dynamics simulations indicating that L-Phe binding and mutation of the conserved N-terminal Trp8 to Ala both promote an inward-facing state. Compared to the outward-facing occluded conformation, our structure reveals a major tilting of the cytoplasmic end of transmembrane segment (TM) 5, which, together with release of the N-terminus but without coupled movement of TM1, opens a wide cavity towards the second Na+ binding site. The structure of this key intermediate in the LeuT transport cycle, in the context of other NSS structures, leads to the proposal of an intracellular release mechanism of substrate and ions in NSS proteins.},
doi = {10.1038/s41467-020-14735-w},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {Fri Feb 21 00:00:00 EST 2020},
month = {Fri Feb 21 00:00:00 EST 2020}
}
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