8fwv
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8fwv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FWV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FWV FirstGlance]. <br> | <table><tr><td colspan='2'>[[8fwv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FWV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FWV FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.03Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=8fwv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fwv OCA], [https://pdbe.org/8fwv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fwv RCSB], [https://www.ebi.ac.uk/pdbsum/8fwv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fwv 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=8fwv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fwv OCA], [https://pdbe.org/8fwv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fwv RCSB], [https://www.ebi.ac.uk/pdbsum/8fwv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fwv ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Kainate receptors (KARs) are a subtype of ionotropic glutamate receptors that control synaptic transmission in the central nervous system and are implicated in neurological, psychiatric, and neurodevelopmental disorders. Understanding the regulation of KAR function by small molecules is essential for exploring these receptors as drug targets. Here, we present cryoelectron microscopy (cryo-EM) structures of KAR GluK2 in complex with the positive allosteric modulator BPAM344, competitive antagonist DNQX, and negative allosteric modulator, antiepileptic drug perampanel. Our structures show that two BPAM344 molecules bind per ligand-binding domain dimer interface. In the absence of an agonist or in the presence of DNQX, BPAM344 stabilizes GluK2 in the closed state. The closed state is also stabilized by perampanel, which binds to the ion channel extracellular collar sites located in two out of four GluK2 subunits. The molecular mechanisms of positive and negative allosteric modulation of KAR provide a guide for developing new therapeutic strategies. | Kainate receptors (KARs) are a subtype of ionotropic glutamate receptors that control synaptic transmission in the central nervous system and are implicated in neurological, psychiatric, and neurodevelopmental disorders. Understanding the regulation of KAR function by small molecules is essential for exploring these receptors as drug targets. Here, we present cryoelectron microscopy (cryo-EM) structures of KAR GluK2 in complex with the positive allosteric modulator BPAM344, competitive antagonist DNQX, and negative allosteric modulator, antiepileptic drug perampanel. Our structures show that two BPAM344 molecules bind per ligand-binding domain dimer interface. In the absence of an agonist or in the presence of DNQX, BPAM344 stabilizes GluK2 in the closed state. The closed state is also stabilized by perampanel, which binds to the ion channel extracellular collar sites located in two out of four GluK2 subunits. The molecular mechanisms of positive and negative allosteric modulation of KAR provide a guide for developing new therapeutic strategies. | ||
| - | Positive and negative allosteric modulation of GluK2 kainate receptors by BPAM344 and antiepileptic perampanel.,Gangwar SP, Yen LY, Yelshanskaya MV, Sobolevsky AI Cell Rep. 2023 Feb | + | Positive and negative allosteric modulation of GluK2 kainate receptors by BPAM344 and antiepileptic perampanel.,Gangwar SP, Yen LY, Yelshanskaya MV, Sobolevsky AI Cell Rep. 2023 Feb 28;42(2):112124. doi: 10.1016/j.celrep.2023.112124. Epub 2023 , Feb 21. PMID:36857176<ref>PMID:36857176</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8fwv" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8fwv" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Structure of the amino-terminal domain of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel
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