6cq9

From Proteopedia

(Difference between revisions)

Revision as of 13:54, 11 April 2018

K2P2.1(TREK-1):ML402 complex

Structural highlights

6cq9 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	6cq8
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.

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6cq9"

Categories: Lolicato, M | Minor, D L | Transport protein | Trek-1 ion channel k2p

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6cq9 is ON HOLD
+==K2P2.1(TREK-1):ML402 complex==
+<StructureSection load='6cq9' size='340' side='right' caption='[[6cq9]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6cq9]] is a 2 chain structure. 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>
+</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>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6cq8|6cq8]]</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>
+== 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>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors: Lolicato, M., Minor, D.L.
+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<ref>PMID:28693035</ref>
-Description: K2P2.1(TREK-1):ML402 complex
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6cq9" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Lolicato, M]]
-[[Category: Minor, D.L]]
+[[Category: Minor, D L]]
+[[Category: Transport protein]]
+[[Category: Trek-1 ion channel k2p]]

6cq9

From Proteopedia

Revision as of 13:54, 11 April 2018

K2P2.1(TREK-1):ML402 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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