7XR4

Structure of human excitatory amino acid transporter 2 (EAAT2) in complex with glutamate

Summary for 7XR4

• Entry DOI: 10.2210/pdb7xr4/pdb
• EMDB information: 33407
• Descriptor: Excitatory amino acid transporter 2, GLUTAMIC ACID, CHOLESTEROL HEMISUCCINATE, ... (4 entities in total)
• Functional Keywords: glutamate transport, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 207359.98

Authors

Zhao, Y.,Zhang, Z. (deposition date: 2022-05-09, release date: 2022-06-22, Last modification date: 2025-07-02)

Primary citation

Zhang, Z.,Chen, H.,Geng, Z.,Yu, Z.,Li, H.,Dong, Y.,Zhang, H.,Huang, Z.,Jiang, J.,Zhao, Y.
Structural basis of ligand binding modes of human EAAT2.
Nat Commun, 13:3329-3329, 2022

PubMed 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.

PubMed: 35680945
DOI: 10.1038/s41467-022-31031-x

Experimental method

ELECTRON MICROSCOPY (3.4 Å)