7wgd

From Proteopedia

(Difference between revisions)

Revision as of 05:33, 8 September 2022

X-ray structure of thermostabilized Drosophila dopamine transporter with GABA transporter1-like substitutions in the binding site, in substrate-free form.

Structural highlights

7wgd is a 3 chain structure with sequence from Drosophila melanogaster and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[DAT_DROME] Sodium-dependent dopamine transporter which terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:11125028, PubMed:12606774, PubMed:24037379, PubMed:25970245). Also transports tyramine and norepinephrine, shows less efficient transport of octopamine and does not transport serotonin (PubMed:11125028, PubMed:12606774). Plays a role in the regulation of the rest/activity cycle (PubMed:16093388, PubMed:25232310).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter, and its levels in the synaptic space are controlled by the GABA transporter isoforms (GATs). GATs are structurally related to biogenic amine transporters but display interactions with distinct inhibitors used as anti-epileptics. In this study, we engineer the binding pocket of Drosophila melanogaster dopamine transporter to resemble GAT1 and determine high-resolution X-ray structures of the modified transporter in the substrate-free state and in complex with GAT1 inhibitors NO711 and SKF89976a that are analogs of tiagabine, a medication prescribed for the treatment of partial seizures. We observe that the primary binding site undergoes substantial shifts in subsite architecture in the modified transporter to accommodate the two GAT1 inhibitors. We also observe that SKF89976a additionally interacts at an allosteric site in the extracellular vestibule, yielding an occluded conformation. Interchanging SKF89976a interacting residue in the extracellular loop 4 between GAT1 and dDAT suggests a role for this motif in the selective control of neurotransmitter uptake. Our findings, therefore, provide vital insights into the organizational principles dictating GAT1 activity and inhibition.

Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter.,Joseph D, Nayak SR, Penmatsa A EMBO J. 2022 Jul 7:e110735. doi: 10.15252/embj.2022110735. PMID:35796008^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Porzgen P, Park SK, Hirsh J, Sonders MS, Amara SG. The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines. Mol Pharmacol. 2001 Jan;59(1):83-95. doi: 10.1124/mol.59.1.83. PMID:11125028 doi:http://dx.doi.org/10.1124/mol.59.1.83
↑ Wu X, Gu HH. Cocaine affinity decreased by mutations of aromatic residue phenylalanine 105 in the transmembrane domain 2 of dopamine transporter. Mol Pharmacol. 2003 Mar;63(3):653-8. doi: 10.1124/mol.63.3.653. PMID:12606774 doi:http://dx.doi.org/10.1124/mol.63.3.653
↑ Kume K, Kume S, Park SK, Hirsh J, Jackson FR. Dopamine is a regulator of arousal in the fruit fly. J Neurosci. 2005 Aug 10;25(32):7377-84. doi: 10.1523/JNEUROSCI.2048-05.2005. PMID:16093388 doi:http://dx.doi.org/10.1523/JNEUROSCI.2048-05.2005
↑ Penmatsa A, Wang KH, Gouaux E. X-ray structure of dopamine transporter elucidates antidepressant mechanism. Nature. 2013 Sep 15. doi: 10.1038/nature12533. PMID:24037379 doi:10.1038/nature12533
↑ Ueno T, Kume K. Functional characterization of dopamine transporter in vivo using Drosophila melanogaster behavioral assays. Front Behav Neurosci. 2014 Sep 3;8:303. doi: 10.3389/fnbeh.2014.00303., eCollection 2014. PMID:25232310 doi:http://dx.doi.org/10.3389/fnbeh.2014.00303
↑ Wang KH, Penmatsa A, Gouaux E. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature. 2015 May 21;521(7552):322-7. doi: 10.1038/nature14431. Epub 2015 May 11. PMID:25970245 doi:http://dx.doi.org/10.1038/nature14431
↑ Joseph D, Nayak SR, Penmatsa A. Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter. EMBO J. 2022 Jul 7:e110735. doi: 10.15252/embj.2022110735. PMID:35796008 doi:http://dx.doi.org/10.15252/embj.2022110735

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7wgd"

Categories: Drosophila melanogaster | Large Structures | Mus musculus | Joseph D | Penmatsa A

@@ Line 3: / Line 3: @@
 <StructureSection load='7wgd' size='340' side='right'caption='[[7wgd]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7wgd]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WGD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WGD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7wgd]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WGD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WGD FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=7wgd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wgd OCA], [https://pdbe.org/7wgd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wgd RCSB], [https://www.ebi.ac.uk/pdbsum/7wgd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wgd ProSAT]</span></td></tr>
 </table>
 == Function ==
 [[https://www.uniprot.org/uniprot/DAT_DROME DAT_DROME]] Sodium-dependent dopamine transporter which terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:11125028, PubMed:12606774, PubMed:24037379, PubMed:25970245). Also transports tyramine and norepinephrine, shows less efficient transport of octopamine and does not transport serotonin (PubMed:11125028, PubMed:12606774). Plays a role in the regulation of the rest/activity cycle (PubMed:16093388, PubMed:25232310).<ref>PMID:11125028</ref> <ref>PMID:12606774</ref> <ref>PMID:16093388</ref> <ref>PMID:24037379</ref> <ref>PMID:25232310</ref> <ref>PMID:25970245</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Drosophila melanogaster]]
 [[Category: Large Structures]]
-[[Category: Joseph, D]]
+[[Category: Mus musculus]]
-[[Category: Penmatsa, A]]
+[[Category: Joseph D]]
-[[Category: Antibody fragment]]
+[[Category: Penmatsa A]]
-[[Category: Gaba transporter]]
-[[Category: Membrane protein]]
-[[Category: Neurotransmitter transporter]]

7wgd

From Proteopedia

Revision as of 05:33, 8 September 2022

X-ray structure of thermostabilized Drosophila dopamine transporter with GABA transporter1-like substitutions in the binding site, in substrate-free form.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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