Structure and allosteric inhibition of excitatory amino acid transporter 1 - Institut Pasteur Accéder directement au contenu
Article Dans Une Revue Nature Année : 2017

Structure and allosteric inhibition of excitatory amino acid transporter 1

Résumé

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 their functions is associated to neurodegenerative disorders and cancer. Here we present the first 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 show novel architectural features of the human transporters, including intra-and extracellular domains with potential roles in transport function, as well as regulation by lipids and post-translational modifications. The coordination of the inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry, reveal an allosteric mechanism of inhibition, whereby the transporter is locked in the outward-facing states of the transport cycle. Our results provide unprecedented insights into the molecular mechanisms of function and pharmacology of human SLC1 transporters. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Fichier principal
Vignette du fichier
17Nature_Canul-Tech-etal_PMC.pdf (6.8 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03053914 , version 1 (05-12-2017)
hal-03053914 , version 2 (11-12-2020)

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

Identifiants

Citer

Juan C Canul-Tec, Reda Assal, Erica Cirri, Pierre Legrand, Sebastien Brier, et al.. Structure and allosteric inhibition of excitatory amino acid transporter 1. Nature, 2017, 544 (7651), pp.446 - 451. ⟨10.1038/nature22064⟩. ⟨hal-03053914v2⟩
342 Consultations
422 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More