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| | <StructureSection load='6cq9' size='340' side='right'caption='[[6cq9]], [[Resolution|resolution]] 2.80Å' scene=''> | | <StructureSection load='6cq9' size='340' side='right'caption='[[6cq9]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cq9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5vkp 5vkp]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CQ9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CQ9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cq9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5vkp 5vkp]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CQ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CQ9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=16C:N-((E,2S,3R)-1,3-DIHYDROXYOCTADEC-4-EN-2-YL)PALMITAMIDE'>16C</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=Q5F:N-[2-(4-chloro-2-methylphenoxy)ethyl]thiophene-2-carboxamide'>Q5F</scene>, <scene name='pdbligand=R16:HEXADECANE'>R16</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]] 2.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6cq8|6cq8]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=16C:N-((E,2S,3R)-1,3-DIHYDROXYOCTADEC-4-EN-2-YL)PALMITAMIDE'>16C</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=Q5F:N-[2-(4-chloro-2-methylphenoxy)ethyl]thiophene-2-carboxamide'>Q5F</scene>, <scene name='pdbligand=R16:HEXADECANE'>R16</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Kcnk2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=6cq9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cq9 OCA], [https://pdbe.org/6cq9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cq9 RCSB], [https://www.ebi.ac.uk/pdbsum/6cq9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cq9 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=6cq9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cq9 OCA], [http://pdbe.org/6cq9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cq9 RCSB], [http://www.ebi.ac.uk/pdbsum/6cq9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cq9 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KCNK2_MOUSE KCNK2_MOUSE]] Ion channel that contributes to passive transmembrane potassium transport. Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward rectifying potassium channel in a phosphorylation-dependent manner. In astrocytes, forms mostly heterodimeric potassium channels with KCNK1, with only a minor proportion of functional channels containing homodimeric KCNK2 (PubMed:24496152). In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1 (PubMed:24496152).<ref>PMID:10321245</ref> <ref>PMID:16636285</ref> <ref>PMID:24496152</ref> <ref>PMID:9003761</ref> | + | [https://www.uniprot.org/uniprot/KCNK2_MOUSE KCNK2_MOUSE] Ion channel that contributes to passive transmembrane potassium transport. Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward rectifying potassium channel in a phosphorylation-dependent manner. In astrocytes, forms mostly heterodimeric potassium channels with KCNK1, with only a minor proportion of functional channels containing homodimeric KCNK2 (PubMed:24496152). In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1 (PubMed:24496152).<ref>PMID:10321245</ref> <ref>PMID:16636285</ref> <ref>PMID:24496152</ref> <ref>PMID:9003761</ref> |
| | <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== |
| - | *[[Potassium Channel|Potassium Channel]] | + | *[[Potassium channel 3D structures|Potassium channel 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Lolicato, M]] | + | [[Category: Lolicato M]] |
| - | [[Category: Minor, D L]] | + | [[Category: Minor DL]] |
| - | [[Category: Transport protein]]
| + | |
| - | [[Category: Trek-1 ion channel k2p]]
| + | |
| Structural highlights
6cq9 is a 2 chain structure with sequence from Mus musculus. This structure supersedes the now removed PDB entry 5vkp. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.8Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
KCNK2_MOUSE Ion channel that contributes to passive transmembrane potassium transport. Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward rectifying potassium channel in a phosphorylation-dependent manner. In astrocytes, forms mostly heterodimeric potassium channels with KCNK1, with only a minor proportion of functional channels containing homodimeric KCNK2 (PubMed:24496152). In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1 (PubMed:24496152).[1] [2] [3] [4]
Publication Abstract from PubMed
Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter 'C-type' gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402-define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation-pi interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate 'leak mode' and provide direct evidence for K2P selectivity filter gating.
K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site.,Lolicato M, Arrigoni C, Mori T, Sekioka Y, Bryant C, Clark KA, Minor DL Jr Nature. 2017 Jul 20;547(7663):364-368. doi: 10.1038/nature22988. Epub 2017 Jul, 10. PMID:28693035[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci. 1999 May;2(5):422-6. PMID:10321245 doi:http://dx.doi.org/10.1038/8084
- ↑ Honore E, Patel AJ, Chemin J, Suchyna T, Sachs F. Desensitization of mechano-gated K2P channels. Proc Natl Acad Sci U S A. 2006 May 2;103(18):6859-64. Epub 2006 Apr 24. PMID:16636285 doi:http://dx.doi.org/10.1073/pnas.0600463103
- ↑ Hwang EM, Kim E, Yarishkin O, Woo DH, Han KS, Park N, Bae Y, Woo J, Kim D, Park M, Lee CJ, Park JY. A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nat Commun. 2014;5:3227. doi: 10.1038/ncomms4227. PMID:24496152 doi:http://dx.doi.org/10.1038/ncomms4227
- ↑ Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C, Lazdunski M. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J. 1996 Dec 16;15(24):6854-62. PMID:9003761
- ↑ Lolicato M, Arrigoni C, Mori T, Sekioka Y, Bryant C, Clark KA, Minor DL Jr. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site. Nature. 2017 Jul 20;547(7663):364-368. doi: 10.1038/nature22988. Epub 2017 Jul, 10. PMID:28693035 doi:http://dx.doi.org/10.1038/nature22988
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