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

Author

Listed:
  • Kamil Gotfryd

    (University of Copenhagen
    University of Copenhagen)

  • Thomas Boesen

    (Aarhus University
    Aarhus University)

  • Jonas S. Mortensen

    (University of Copenhagen)

  • George Khelashvili

    (Cornell University)

  • Matthias Quick

    (Columbia University Vagelos College of Physicians & Surgeon and Division of Molecular Therapeutics, New York State Psychiatric Institute)

  • Daniel S. Terry

    (St. Jude Children’s Research Hospital)

  • Julie W. Missel

    (University of Copenhagen)

  • Michael V. LeVine

    (Cornell University)

  • Pontus Gourdon

    (University of Copenhagen)

  • Scott C. Blanchard

    (St. Jude Children’s Research Hospital)

  • Jonathan A. Javitch

    (Columbia University Vagelos College of Physicians & Surgeon and Division of Molecular Therapeutics, New York State Psychiatric Institute)

  • Harel Weinstein

    (Cornell University)

  • Claus J. Loland

    (University of Copenhagen)

  • Poul Nissen

    (Aarhus University
    Aarhus University)

  • Ulrik Gether

    (University of Copenhagen)

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.

Suggested Citation

  • Kamil Gotfryd & Thomas Boesen & Jonas S. Mortensen & George Khelashvili & Matthias Quick & Daniel S. Terry & Julie W. Missel & Michael V. LeVine & Pontus Gourdon & Scott C. Blanchard & Jonathan A. Jav, 2020. "X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14735-w
    DOI: 10.1038/s41467-020-14735-w
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    Cited by:

    1. Huanyu Z. Li & Ashley C. W. Pike & Irina Lotsaris & Gamma Chi & Jesper S. Hansen & Sarah C. Lee & Karin E. J. Rödström & Simon R. Bushell & David Speedman & Adam Evans & Dong Wang & Didi He & Leela Sh, 2024. "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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