7VR8

Inward-facing structure of human EAAT2 in the substrate-free state

7VR8 の概要

• エントリーDOI: 10.2210/pdb7vr8/pdb
• EMDBエントリー: 32098
• 分子名称: Excitatory amino acid transporter 2, (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en, CHOLESTEROL, ... (4 entities in total)
• 機能のキーワード: transporter, membrane protein, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 65528.63

構造登録者

Kato, T.,Kusakizako, T.,Yamashita, K.,Nishizawa, T.,Nureki, O. (登録日: 2021-10-22, 公開日: 2022-08-10, 最終更新日: 2024-06-26)

主引用文献

Kato, T.,Kusakizako, T.,Jin, C.,Zhou, X.,Ohgaki, R.,Quan, L.,Xu, M.,Okuda, S.,Kobayashi, K.,Yamashita, K.,Nishizawa, T.,Kanai, Y.,Nureki, O.
Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2.
Nat Commun, 13:4714-4714, 2022

PubMed Abstract: Glutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial transporter, Excitatory Amino Acid Transporter 2 (EAAT2), belonging to the SLC1A family. However, in some cancers, EAAT2 expression is enhanced and causes resistance to therapies by metabolic disturbance. Despite its crucial roles, the detailed structural information about EAAT2 has not been available. Here, we report cryo-EM structures of human EAAT2 in substrate-free and selective inhibitor WAY213613-bound states at 3.2 Å and 2.8 Å, respectively. EAAT2 forms a trimer, with each protomer consisting of transport and scaffold domains. Along with a glutamate-binding site, the transport domain possesses a cavity that could be disrupted during the transport cycle. WAY213613 occupies both the glutamate-binding site and cavity of EAAT2 to interfere with its alternating access, where the sensitivity is defined by the inner environment of the cavity. We provide the characterization of the molecular features of EAAT2 and its selective inhibition mechanism that may facilitate structure-based drug design for EAAT2.

PubMed: 35953475
DOI: 10.1038/s41467-022-32442-6

実験手法

ELECTRON MICROSCOPY (3.58 Å)