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Nature. 2017 Apr 27;544(7651):446-451. doi: 10.1038/nature22064. Epub 2017 Apr 19.

Structure and allosteric inhibition of excitatory amino acid transporter 1.

Author information

1
Molecular Mechanisms of Membrane Transport Laboratory, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France.
2
UMR 3528, CNRS, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France.
3
Synchrotron SOLEIL, L'Orme des Merisiers, 91192 Gif-sur-Yvette, France.
4
Structural Mass Spectrometry and Proteomics Unit, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France.
#
Contributed equally

Abstract

Human members of the solute carrier 1 (SLC1) family of transporters take up excitatory neurotransmitters in the brain and amino acids in peripheral organs. Dysregulation of the function of SLC1 transporters is associated with neurodegenerative disorders and cancer. Here we present crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter 1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures reveal architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids and post-translational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry reveal a mechanism of inhibition, in which the transporter is locked in the outward-facing states of the transport cycle. Our results provide insights into the molecular mechanisms underlying the function and pharmacology of human SLC1 transporters.

PMID:
28424515
PMCID:
PMC5410168
DOI:
10.1038/nature22064
[Indexed for MEDLINE]
Free PMC Article

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