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==Human excitatory amino acid transporter 3 (EAAT3) with bound L-Aspartate in an intermediate outward facing state==
<StructureSection load='9d66' size='340' side='right'caption='[[9d66]], [[Resolution|resolution]] 2.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9d66]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9D66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9D66 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.98&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ASP:ASPARTIC+ACID'>ASP</scene>, <scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9d66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9d66 OCA], [https://pdbe.org/9d66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9d66 RCSB], [https://www.ebi.ac.uk/pdbsum/9d66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9d66 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/EAA3_HUMAN EAA3_HUMAN] Hot water reflex epilepsy;Dicarboxylic aminoaciduria. The disease is caused by variants affecting the gene represented in this entry.  Disease susceptibility is associated with variants affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders (PubMed:21982423). This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members (PubMed:23341099).<ref>PMID:21982423</ref> <ref>PMID:23341099</ref> 
== Function ==
[https://www.uniprot.org/uniprot/EAA3_HUMAN EAA3_HUMAN] Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:21123949, PubMed:26690923, PubMed:33658209, PubMed:7521911, PubMed:7914198, PubMed:8857541). Can also transport L-cysteine (PubMed:21123949). 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:26690923, PubMed:33658209, PubMed:7521911, PubMed:8857541). 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:26690923, PubMed:8857541). Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli (PubMed:21123949). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (By similarity). Contributes to glutathione biosynthesis and protection against oxidative stress via its role in L-glutamate and L-cysteine transport (By similarity). Negatively regulated by ARL6IP5 (By similarity).[UniProtKB:P51906][UniProtKB:P51907]<ref>PMID:21123949</ref> <ref>PMID:26690923</ref> <ref>PMID:33658209</ref> <ref>PMID:7521911</ref> <ref>PMID:7914198</ref> <ref>PMID:8857541</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Excitatory amino acid transporters (EAATs) reside on cell surfaces and uptake substrates, including L-glutamate, L-aspartate, and D-aspartate, using ion gradients. Among five EAATs, EAAT3 is the only isoform that can efficiently transport L-cysteine, a substrate for glutathione synthesis. Recent work suggests that EAAT3 also transports the oncometabolite R-2-hydroxyglutarate (R-2HG). Here, we examined the structural basis of substrate promiscuity by determining the cryo-EM structures of EAAT3 bound to different substrates. We found that L-cysteine binds to EAAT3 in thiolate form, and EAAT3 recognizes different substrates by fine-tuning local conformations of the coordinating residues. However, using purified human EAAT3, we could not observe R-2HG binding or transport. Imaging of EAAT3 bound to L-cysteine revealed several conformational states, including an outward-facing state with a semi-open gate and a disrupted sodium-binding site. These structures illustrate that the full gate closure, coupled with the binding of the last sodium ion, occurs after substrate binding. Furthermore, we observed that different substrates affect how the transporter distributes between a fully outward-facing conformation and intermediate occluded states on a path to the inward-facing conformation, suggesting that translocation rates are substrate-dependent.

Structural basis of the excitatory amino acid transporter 3 substrate recognition.,Qiu B, Boudker O bioRxiv [Preprint]. 2024 Sep 8:2024.09.05.611541. doi: 10.1101/2024.09.05.611541. PMID:39282329<ref>PMID:39282329</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9d66" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Boudker O]]
[[Category: Qiu B]]