5MJU

Structure of the thermostabilized EAAT1 cryst mutant in complex with the competititve inhibitor TFB-TBOA and the allosteric inhibitor UCPH101

5MJU の概要

• エントリーDOI: 10.2210/pdb5mju/pdb
• 分子名称: Excitatory amino acid transporter 1,Neutral amino acid transporter B(0),Excitatory amino acid transporter 1, 2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-4H-chromene-3-carbonitrile, (2~{S},3~{S})-2-azanyl-3-[[3-[[4-(trifluoromethyl)phenyl]carbonylamino]phenyl]methoxy]butanedioic acid (3 entities in total)
• 機能のキーワード: excitatory aminoacid transporter 1, human glutamate transporter, tfb-tboa, ucph-101, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Multi-pass membrane protein: P43003
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57361.20

構造登録者

Canul-Tec, J.,Assal, R.,Legrand, P.,Reyes, N. (登録日: 2016-12-01, 公開日: 2017-04-19, 最終更新日: 2024-01-17)

主引用文献

Canul-Tec, J.C.,Assal, R.,Cirri, E.,Legrand, P.,Brier, S.,Chamot-Rooke, J.,Reyes, N.
Structure and allosteric inhibition of excitatory amino acid transporter 1.
Nature, 544:446-451, 2017

PubMed 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.

PubMed: 28424515
DOI: 10.1038/nature22064

実験手法

X-RAY DIFFRACTION (3.71 Å)