Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 08 2022
11 08 2022
Historique:
received:
01
11
2021
accepted:
01
08
2022
entrez:
11
8
2022
pubmed:
12
8
2022
medline:
16
8
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35953475
doi: 10.1038/s41467-022-32442-6
pii: 10.1038/s41467-022-32442-6
pmc: PMC9372063
doi:
Substances chimiques
Excitatory Amino Acid Transporter 2
0
Excitatory Amino Acid Transporter 3
0
SLC1A2 protein, human
0
Glutamic Acid
3KX376GY7L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4714Informations de copyright
© 2022. The Author(s).
Références
Acta Crystallogr D Struct Biol. 2021 Oct 1;77(Pt 10):1282-1291
pubmed: 34605431
Pathol Oncol Res. 2015 Jul;21(3):759-64
pubmed: 25576211
Front Mol Biosci. 2019 Oct 23;6:110
pubmed: 31709262
Schizophr Res. 2010 Mar;117(1):92-8
pubmed: 19716271
Nat Struct Mol Biol. 2013 Oct;20(10):1224-6
pubmed: 24013209
PLoS Genet. 2013 Apr;9(4):e1003464
pubmed: 23637631
Nat Commun. 2019 Jul 31;10(1):3427
pubmed: 31366933
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5
pubmed: 20057045
Nature. 2021 Mar;591(7849):327-331
pubmed: 33597752
Bioorg Med Chem Lett. 2005 Nov 15;15(22):4985-8
pubmed: 16165356
Nat Commun. 2016 Nov 10;7:13420
pubmed: 27830699
Nat Rev Neurosci. 2002 Sep;3(9):748-55
pubmed: 12209123
Nat Protoc. 2015 Jun;10(6):845-58
pubmed: 25950237
J Struct Biol. 2015 Nov;192(2):216-21
pubmed: 26278980
EMBO J. 2022 Jan 4;41(1):e108341
pubmed: 34747040
Cell Biochem Biophys. 2017 Dec;75(3-4):369-385
pubmed: 28417231
Nat Struct Mol Biol. 2018 Jun;25(6):515-521
pubmed: 29872227
Biochem Soc Trans. 2020 Jun 30;48(3):1227-1241
pubmed: 32369548
Brain Pathol. 2002 Oct;12(4):405-11
pubmed: 12408226
Acta Crystallogr D Biol Crystallogr. 2009 Oct;65(Pt 10):1074-80
pubmed: 19770504
Protein Sci. 2010 Dec;19(12):2389-401
pubmed: 20945358
Sci Adv. 2021 Mar 3;7(10):
pubmed: 33658209
Am J Hum Genet. 2017 Aug 3;101(2):300-310
pubmed: 28777935
Nature. 2009 Dec 17;462(7275):880-5
pubmed: 19924125
Biochem J. 2011 Jun 1;436(2):193-211
pubmed: 21568940
Nature. 2007 Jan 25;445(7126):387-93
pubmed: 17230192
Trends Biochem Sci. 2018 Oct;43(10):752-789
pubmed: 30177408
Brain Res. 2010 Feb 26;1316:27-34
pubmed: 20026319
Ann Neurol. 1995 Jul;38(1):73-84
pubmed: 7611729
IUCrJ. 2019 Jan 01;6(Pt 1):5-17
pubmed: 30713699
Biochim Biophys Acta Mol Basis Dis. 2021 May 1;1867(5):166079
pubmed: 33476785
Cell Rep. 2019 Jul 2;28(1):104-118.e8
pubmed: 31269432
Elife. 2019 Oct 03;8:
pubmed: 31580259
Front Cell Neurosci. 2020 Apr 24;14:90
pubmed: 32390802
Nat Commun. 2020 Feb 21;11(1):998
pubmed: 32081874
Nature. 2004 Oct 14;431(7010):811-8
pubmed: 15483603
Neuropharmacology. 2005 Mar;48(4):479-91
pubmed: 15755476
Sci Rep. 2017 Mar 03;7:42717
pubmed: 28256516
Cell Res. 2022 Jul;32(7):638-658
pubmed: 35459936
Nature. 2015 Feb 5;518(7537):68-73
pubmed: 25652997
ACS Chem Neurosci. 2019 Aug 21;10(8):3437-3453
pubmed: 31257852
J Biol Chem. 2001 Jan 5;276(1):576-82
pubmed: 11031254
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
ACS Chem Neurosci. 2020 Jun 3;11(11):1573-1596
pubmed: 32343555
Nat Struct Mol Biol. 2019 Jun;26(6):510-517
pubmed: 31160781
J Biol Chem. 2004 Aug 13;279(33):34388-96
pubmed: 15187084
Acta Crystallogr D Struct Biol. 2018 Mar 1;74(Pt 3):215-227
pubmed: 29533229
Glia. 2020 Dec;68(12):2631-2642
pubmed: 32585762
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Exp Neurol. 2016 Sep;283(Pt A):85-96
pubmed: 27155358
Comput Struct Biotechnol J. 2021 Sep 17;19:5246-5254
pubmed: 34630942
Elife. 2018 Nov 09;7:
pubmed: 30412051
Ann Neurol. 1998 May;43(5):645-53
pubmed: 9585360
Neurochem Res. 2020 Jun;45(6):1268-1286
pubmed: 31981058
J Struct Biol. 2020 Aug 1;211(2):107545
pubmed: 32534144
ChemMedChem. 2016 Jun 6;11(11):1117-21
pubmed: 27218427
J Biomed Res. 2019 Oct 31;34(4):260-270
pubmed: 32594024
J Neurosci. 2004 Feb 4;24(5):1136-48
pubmed: 14762132
Ann Neurol. 1996 Nov;40(5):759-66
pubmed: 8957017
Schizophr Res. 2013 Mar;144(1-3):1-8
pubmed: 23356950
Nat Methods. 2017 Apr;14(4):331-332
pubmed: 28250466
Neurosci Lett. 2022 May 29;780:136637
pubmed: 35439550
ACS Chem Neurosci. 2018 Mar 21;9(3):522-534
pubmed: 29140675
Biophys J. 2006 Nov 15;91(10):3718-26
pubmed: 16950847
Mol Pharmacol. 1998 Feb;53(2):195-201
pubmed: 9463476
Nat Protoc. 2014 Nov;9(11):2574-85
pubmed: 25299155
Science. 1997 Jun 13;276(5319):1699-702
pubmed: 9180080
Nature. 2017 Apr 27;544(7651):446-451
pubmed: 28424515
Brain Res Brain Res Rev. 1998 May;26(2-3):230-5
pubmed: 9651535
Sci Transl Med. 2011 Apr 6;3(77):77ra30
pubmed: 21471434
Eur J Hum Genet. 2015 Sep;23(9):1200-6
pubmed: 25406999
J Neurosci. 1998 Nov 1;18(21):8751-7
pubmed: 9786982
J Neurochem. 2010 May;113(4):978-89
pubmed: 20193040