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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='5v03' size='340' side='right' caption='[[5v03]], [[Resolution|resolution]] 1.58Å' scene=''> | + | <StructureSection load='5v03' size='340' side='right'caption='[[5v03]], [[Resolution|resolution]] 1.58Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5v03]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V03 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V03 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5v03]] 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=5V03 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V03 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=658:N-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine'>658</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</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]] 1.58Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v02|5v02]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=658:N-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-amine'>658</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KCNN2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CALM1, CALM, CAM, CAM1, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5v03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v03 OCA], [https://pdbe.org/5v03 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v03 RCSB], [https://www.ebi.ac.uk/pdbsum/5v03 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v03 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5v03 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v03 OCA], [http://pdbe.org/5v03 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v03 RCSB], [http://www.ebi.ac.uk/pdbsum/5v03 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v03 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Calmodulin|Calmodulin]] | + | *[[Calmodulin 3D structures|Calmodulin 3D structures]] |
| | + | *[[Potassium channel 3D structures|Potassium channel 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Liu, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Activator]] | + | [[Category: Liu S]] |
| - | [[Category: Calcium-activated ion channel]]
| + | |
| - | [[Category: Calmodulin]]
| + | |
| - | [[Category: Transport protein-metal binding protein complex]]
| + | |
| Structural highlights
Function
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. An Intracellular Allosteric Modulator Binding Pocket in SK2 Ion Channels Is Shared by Multiple Chemotypes. Structure. 2018 Apr 3;26(4):533-544.e3. doi: 10.1016/j.str.2018.02.017. Epub 2018, Mar 22. PMID:29576321 doi:http://dx.doi.org/10.1016/j.str.2018.02.017
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