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TitleStructural basis of ligand binding modes of human EAAT2.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 3329, Year 2022
Publish dateJun 9, 2022
AuthorsZhenglai Zhang / Huiwen Chen / Ze Geng / Zhuoya Yu / Hang Li / Yanli Dong / Hongwei Zhang / Zhuo Huang / Juquan Jiang / Yan Zhao /
PubMed AbstractIn 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 ...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.
External linksNat Commun / PubMed:35680945 / PubMed Central
MethodsEM (single particle)
Resolution3.4 Å
Structure data

33407

7xr4

EMDB-33407, PDB-7xr4:
Structure of human excitatory amino acid transporter 2 (EAAT2) in complex with glutamate
Method: EM (single particle) / Resolution: 3.4 Å

33408

7xr6

EMDB-33408, PDB-7xr6:
Structure of human excitatory amino acid transporter 2 (EAAT2) in complex with WAY-213613
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-GLU:
GLUTAMIC ACID

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

ChemComp-GJ0:
(2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid / inhibitor*YM

ChemComp-XKJ:
dodecyl beta-D-glucopyranoside / detergent*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Glutamate transport

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