Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2

Takafumi Kato, Tsukasa Kusakizako (), Chunhuan Jin, Xinyu Zhou, Ryuichi Ohgaki, LiLi Quan, Minhui Xu, Suguru Okuda, Kan Kobayashi, Keitaro Yamashita, Tomohiro Nishizawa, Yoshikatsu Kanai () and Osamu Nureki ()
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Takafumi Kato: The University of Tokyo
Tsukasa Kusakizako: The University of Tokyo
Chunhuan Jin: Osaka University
Xinyu Zhou: Osaka University
Ryuichi Ohgaki: Osaka University
LiLi Quan: Osaka University
Minhui Xu: Osaka University
Suguru Okuda: Osaka University
Kan Kobayashi: The University of Tokyo
Keitaro Yamashita: The University of Tokyo
Tomohiro Nishizawa: The University of Tokyo
Yoshikatsu Kanai: Osaka University
Osamu Nureki: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32442-6

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