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

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. Javitch, Harel Weinstein, Claus J. Loland (), Poul Nissen () and Ulrik Gether ()
Additional contact information
Kamil Gotfryd: University of Copenhagen
Thomas Boesen: 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
Ulrik Gether: University of Copenhagen

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-020-14735-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14735-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-14735-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().