7vr8
Inward-facing structure of human EAAT2 in the substrate-free state
Structural highlights
Disease[EAA2_HUMAN] Non-specific early-onset epileptic encephalopathy. The disease is caused by variants affecting the gene represented in this entry. Function[EAA2_HUMAN] Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7521911, PubMed:14506254, PubMed:15265858, PubMed:26690923). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:14506254). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:14506254). Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate (By similarity).[UniProtKB:P43006][1] [2] [3] Publication Abstract from PubMedGlutamate 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 A and 2.8 A, 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. Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2.,Kato T, Kusakizako T, Jin C, Zhou X, Ohgaki R, Quan L, Xu M, Okuda S, Kobayashi K, Yamashita K, Nishizawa T, Kanai Y, Nureki O Nat Commun. 2022 Aug 11;13(1):4714. doi: 10.1038/s41467-022-32442-6. PMID:35953475[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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