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<StructureSection load='7sk2' size='340' side='right'caption='[[7sk2]], [[Resolution|resolution]] 3.82&Aring;' scene=''>
<StructureSection load='7sk2' size='340' side='right'caption='[[7sk2]], [[Resolution|resolution]] 3.82&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7sk2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SK2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SK2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[7sk2]] is a 1 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=7SK2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SK2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TGI:Tiagabine'>TGI</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TGI:Tiagabine'>TGI</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=7sk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sk2 OCA], [https://pdbe.org/7sk2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sk2 RCSB], [https://www.ebi.ac.uk/pdbsum/7sk2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sk2 ProSAT]</span></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=7sk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sk2 OCA], [https://pdbe.org/7sk2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sk2 RCSB], [https://www.ebi.ac.uk/pdbsum/7sk2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sk2 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[https://www.uniprot.org/uniprot/SC6A1_HUMAN SC6A1_HUMAN]] Myoclonic-astatic epilepsy. The disease is caused by variants affecting the gene represented in this entry.  
[[https://www.uniprot.org/uniprot/SC6A1_HUMAN SC6A1_HUMAN]] Myoclonic-astatic epilepsy. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/SC6A1_HUMAN SC6A1_HUMAN]] Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals.  
[[https://www.uniprot.org/uniprot/SC6A1_HUMAN SC6A1_HUMAN]] Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
gamma-Aminobutyric acid (GABA) transporter 1 (GAT1)(1) regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy(2). Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine(3), with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition(4). The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins.
 
Structural basis of GABA reuptake inhibition.,Motiwala Z, Aduri NG, Shaye H, Han GW, Lam JH, Katritch V, Cherezov V, Gati C Nature. 2022 Jun 8. pii: 10.1038/s41586-022-04814-x. doi:, 10.1038/s41586-022-04814-x. PMID:35676483<ref>PMID:35676483</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7sk2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Aduri, N G]]
[[Category: Aduri NG]]
[[Category: Cherezov, V]]
[[Category: Cherezov V]]
[[Category: Gati, C]]
[[Category: Gati C]]
[[Category: Han, G W]]
[[Category: Han GW]]
[[Category: Motiwala, Z]]
[[Category: Motiwala Z]]
[[Category: Shaye, H]]
[[Category: Shaye H]]
[[Category: Membrane protein]]
[[Category: Neurotransmitter transporter]]

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