6xsr: Difference between revisions
New page: '''Unreleased structure''' The entry 6xsr is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal structure of GluA2 AMPA receptor in complex with trans-4-butylcyclohexane carboxylic acid (4-BCCA) inhibitor== | ||
<StructureSection load='6xsr' size='340' side='right'caption='[[6xsr]], [[Resolution|resolution]] 4.25Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XSR FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 4.25Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=V8G:trans-4-butylcyclohexane-1-carboxylic+acid'>V8G</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=6xsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xsr OCA], [https://pdbe.org/6xsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xsr RCSB], [https://www.ebi.ac.uk/pdbsum/6xsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xsr ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACKGROUND AND PURPOSE: AMPA receptors, which shape excitatory postsynaptic currents and are directly involved in overactivation of synaptic function during seizures, represent a well-accepted target for anti-epileptic drugs. Trans-4-butylcyclohexane carboxylic acid (4-BCCA) has emerged as a new promising anti-epileptic drug in several in vitro and in vivo seizure models, but the mechanism of its action remained unknown. The purpose of this study is to characterize structure and dynamics of 4-BCCA interaction with AMPA receptors. EXPERIMENTAL APPROACH: We studied the molecular mechanism of AMPA receptor inhibition by 4-BCCA using a combination of X-ray crystallography, mutagenesis, electrophysiological assays, and molecular dynamics simulations. KEY RESULTS: We identified 4-BCCA binding sites in the transmembrane domain (TMD) of AMPA receptor, at the lateral portals formed by transmembrane segments M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses, and can enter the ion channel pore. CONCLUSION AND IMPLICATIONS: 4-BCCA represents a low-affinity inhibitor of AMPA receptors that acts at the TMD sites distinct from non-competitive inhibitors, such as the anti-epileptic drug perampanel and the ion channel blockers. Further studies might examine the possibsility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas. | |||
Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid.,Yelshanskaya MV, Singh AK, Narangoda C, Williams RSB, Kurnikova MG, Sobolevsky AI Br J Pharmacol. 2020 Sep 22. doi: 10.1111/bph.15254. PMID:32959886<ref>PMID:32959886</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6xsr" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Singh AK]] | |||
[[Category: Sobolevsky AI]] | |||
[[Category: Yelshanskaya MV]] | |||
Latest revision as of 14:24, 30 October 2024
Crystal structure of GluA2 AMPA receptor in complex with trans-4-butylcyclohexane carboxylic acid (4-BCCA) inhibitorCrystal structure of GluA2 AMPA receptor in complex with trans-4-butylcyclohexane carboxylic acid (4-BCCA) inhibitor
Structural highlights
Publication Abstract from PubMedBACKGROUND AND PURPOSE: AMPA receptors, which shape excitatory postsynaptic currents and are directly involved in overactivation of synaptic function during seizures, represent a well-accepted target for anti-epileptic drugs. Trans-4-butylcyclohexane carboxylic acid (4-BCCA) has emerged as a new promising anti-epileptic drug in several in vitro and in vivo seizure models, but the mechanism of its action remained unknown. The purpose of this study is to characterize structure and dynamics of 4-BCCA interaction with AMPA receptors. EXPERIMENTAL APPROACH: We studied the molecular mechanism of AMPA receptor inhibition by 4-BCCA using a combination of X-ray crystallography, mutagenesis, electrophysiological assays, and molecular dynamics simulations. KEY RESULTS: We identified 4-BCCA binding sites in the transmembrane domain (TMD) of AMPA receptor, at the lateral portals formed by transmembrane segments M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses, and can enter the ion channel pore. CONCLUSION AND IMPLICATIONS: 4-BCCA represents a low-affinity inhibitor of AMPA receptors that acts at the TMD sites distinct from non-competitive inhibitors, such as the anti-epileptic drug perampanel and the ion channel blockers. Further studies might examine the possibsility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas. Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid.,Yelshanskaya MV, Singh AK, Narangoda C, Williams RSB, Kurnikova MG, Sobolevsky AI Br J Pharmacol. 2020 Sep 22. doi: 10.1111/bph.15254. PMID:32959886[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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