2. Academic Validation
  3. Structural basis of ligand binding modes of human EAAT2

Structural basis of ligand binding modes of human EAAT2

  • Nat Commun. 2022 Jun 9;13(1):3329. doi: 10.1038/s41467-022-31031-x.
Zhenglai Zhang  # 1 2,  Huiwen Chen  # 1 2,  Ze Geng  # 3 4,  Zhuoya Yu 2 5 6,  Hang Li 2 6,  Yanli Dong 2,  Hongwei Zhang 2 6,  Zhuo Huang 7 8,  Juquan Jiang 9,  Yan Zhao 10 11 12
Affiliations

Affiliations

  • 1 Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, No. 600 Changjiang Road, Xiangfang District, Harbin, 150030, China.
  • 2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 4 IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China.
  • 5 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.
  • 6 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 7 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China. huangz@hsc.pku.edu.cn.
  • 8 IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China. huangz@hsc.pku.edu.cn.
  • 9 Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, No. 600 Changjiang Road, Xiangfang District, Harbin, 150030, China. jjqdainty@163.com.
  • 10 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhaoy@ibp.ac.cn.
  • 11 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China. zhaoy@ibp.ac.cn.
  • 12 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. zhaoy@ibp.ac.cn.
  • # Contributed equally.
PMID: 35680945 DOI: 10.1038/s41467-022-31031-x
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.

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