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TitleStructural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 4714, Year 2022
Publish dateAug 11, 2022
AuthorsTakafumi Kato / Tsukasa Kusakizako / Chunhuan Jin / Xinyu Zhou / Ryuichi Ohgaki / LiLi Quan / Minhui Xu / Suguru Okuda / Kan Kobayashi / Keitaro Yamashita / Tomohiro Nishizawa / Yoshikatsu Kanai / Osamu Nureki /
PubMed AbstractGlutamate is a pivotal excitatory neurotransmitter in mammalian brains, but excessive glutamate causes numerous neural disorders. Almost all extracellular glutamate is retrieved by the glial ...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.
External linksNat Commun / PubMed:35953475 / PubMed Central
MethodsEM (single particle)
Resolution3.49 - 3.58 Å
Structure data

32097

7vr7

EMDB-32097, PDB-7vr7:
Inward-facing structure of human EAAT2 in the WAY213613-bound state
Method: EM (single particle) / Resolution: 3.49 Å

32098

7vr8

EMDB-32098, PDB-7vr8:
Inward-facing structure of human EAAT2 in the substrate-free state
Method: EM (single particle) / Resolution: 3.58 Å

Chemicals

ChemComp-GJ0:
(2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid / inhibitor*YM / WAY-213,613

ChemComp-9Z9:
(3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en / detergent*YM

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / transporter / MEMBRANE PROTEIN

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