X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release

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

doi:10.1038/s41467-020-14735-w

X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release

Journal Article · Fri Feb 21 00:00:00 EST 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-14735-w· OSTI ID:1624251

^[1]; ^[2]; Mortensen, Jonas S. ^[3]; ^[4]; Quick, Matthias ^[5]; Terry, Daniel S. ^[6]; ^[7]; LeVine, Michael V. ^[8]; ^[7]; ^[9]; Javitch, Jonathan A. ^[10]; ^[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; DOE/OSTI
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

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231; AC05-00OR22725

OSTI ID:: 1624251

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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