5v02
From Proteopedia
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==A positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA== | ==A positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA== | ||
| - | <StructureSection load='5v02' size='340' side='right' caption='[[5v02]], [[Resolution|resolution]] 1.78Å' scene=''> | + | <StructureSection load='5v02' size='340' side='right'caption='[[5v02]], [[Resolution|resolution]] 1.78Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5v02]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V02 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5v02]] is a 2 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=5V02 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V02 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=657:6-(trifluoromethoxy)-1,3-benzothiazol-2-amine'>657</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.78Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=657:6-(trifluoromethoxy)-1,3-benzothiazol-2-amine'>657</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5v02 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v02 OCA], [https://pdbe.org/5v02 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v02 RCSB], [https://www.ebi.ac.uk/pdbsum/5v02 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v02 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == Disease == | ||
| - | [[http://www.uniprot.org/uniprot/CALM1_HUMAN CALM1_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. | ||
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/KCNN2_HUMAN KCNN2_HUMAN] Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin. |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Small conductance potassium (SK) ion channels define neuronal firing rates by conducting the after-hyperpolarization current. They are key targets in developing therapies where neuronal firing rates are dysfunctional, such as in epilepsy, Parkinson's, and amyotrophic lateral sclerosis (ALS). Here, we characterize a binding pocket situated at the intracellular interface of SK2 and calmodulin, which we show to be shared by multiple small-molecule chemotypes. Crystallization of this complex revealed that riluzole (approved for ALS) and an analog of the anti-ataxic agent (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-amine (CyPPA) bind to and allosterically modulate via this site. Solution-state nuclear magnetic resonance demonstrates that riluzole, NS309, and CyPPA analogs bind at this bipartite pocket. We demonstrate, by patch-clamp electrophysiology, that both classes of ligand interact with overlapping but distinct residues within this pocket. These data define a clinically important site, laying the foundations for further studies of the mechanism of action of riluzole and related molecules. | ||
| + | |||
| + | An Intracellular Allosteric Modulator Binding Pocket in SK2 Ion Channels Is Shared by Multiple Chemotypes.,Cho LT, Alexandrou AJ, Torella R, Knafels J, Hobbs J, Taylor T, Loucif A, Konopacka A, Bell S, Stevens EB, Pandit J, Horst R, Withka JM, Pryde DC, Liu S, Young GT Structure. 2018 Apr 3;26(4):533-544.e3. doi: 10.1016/j.str.2018.02.017. Epub 2018, Mar 22. PMID:29576321<ref>PMID:29576321</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5v02" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Calmodulin 3D structures|Calmodulin 3D structures]] | ||
| + | *[[Potassium channel 3D structures|Potassium channel 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Liu S]] |
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Current revision
A positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA
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