Structural basis of ligand binding modes of human EAAT2

Zhenglai Zhang, Huiwen Chen, Ze Geng, Zhuoya Yu, Hang Li, Yanli Dong, Hongwei Zhang, Zhuo Huang (), Juquan Jiang () and Yan Zhao ()
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Zhenglai Zhang: Northeast Agricultural University
Huiwen Chen: Northeast Agricultural University
Ze Geng: Peking University Health Science Center
Zhuoya Yu: Chinese Academy of Sciences
Hang Li: Chinese Academy of Sciences
Yanli Dong: Chinese Academy of Sciences
Hongwei Zhang: Chinese Academy of Sciences
Zhuo Huang: Peking University Health Science Center
Juquan Jiang: Northeast Agricultural University
Yan Zhao: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract In the central nervous system (CNS), excitatory amino acid transporters (EAATs) mediate the uptake of excitatory neurotransmitter glutamate and maintain its low concentrations in the synaptic cleft for avoiding neuronal cytotoxicity. Dysfunction of EAATs can lead to many psychiatric diseases. Here we report cryo-EM structures of human EAAT2 in an inward-facing conformation, in the presence of substrate glutamate or selective inhibitor WAY-213613. The glutamate is coordinated by extensive hydrogen bonds and further stabilized by HP2. The inhibitor WAY-213613 occupies a similar binding pocket to that of the substrate glutamate. Upon association with the WAY-213613, the HP2 undergoes a substantial conformational change, and in turn stabilizes the inhibitor binding by forming hydrophobic interactions. Electrophysiological experiments elucidate that the unique S441 plays pivotal roles in the binding of hEAAT2 with glutamate or WAY-213613, and the I464-L467-V468 cluster acts as a key structural determinant for the selective inhibition of this transporter by WAY-213613.

Date: 2022
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DOI: 10.1038/s41467-022-31031-x

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