6v3c

K2P2.1(TREK-1)I110D:Ru360 bound channel structureK2P2.1(TREK-1)I110D:Ru360 bound channel structure

Structural highlights

6v3c is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.51Å
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

The trinuclear ruthenium amine ruthenium red (RuR) inhibits diverse ion channels, including K2P potassium channels, TRPs, the calcium uniporter, CALHMs, ryanodine receptors, and Piezos. Despite this extraordinary array, there is limited information for how RuR engages targets. Here, using X-ray crystallographic and electrophysiological studies of an RuR-sensitive K2P, K2P2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the "Keystone inhibitor site" under the K2P CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect K2Ps, inhibits RuR-sensitive K2Ps using the same mechanism. Structural knowledge enabled a generalizable design strategy for creating K2P RuR "super-responders" having nanomolar sensitivity. Together, the data define a "finger in the dam" inhibition mechanism acting at a novel K2P inhibitor binding site. These findings highlight the polysite nature of K2P pharmacology and provide a new framework for K2P inhibitor development.

Polynuclear Ruthenium Amines Inhibit K2P Channels via a "Finger in the Dam" Mechanism.,Pope L, Lolicato M, Minor DL Jr Cell Chem Biol. 2020 Feb 10. pii: S2451-9456(20)30036-2. doi:, 10.1016/j.chembiol.2020.01.011. PMID:32059793^[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
↑ Pope L, Lolicato M, Minor DL Jr. Polynuclear Ruthenium Amines Inhibit K2P Channels via a "Finger in the Dam" Mechanism. Cell Chem Biol. 2020 Feb 10. pii: S2451-9456(20)30036-2. doi:, 10.1016/j.chembiol.2020.01.011. PMID:32059793 doi:http://dx.doi.org/10.1016/j.chembiol.2020.01.011

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] Pope L, Lolicato M, Minor DL Jr. Polynuclear Ruthenium Amines Inhibit K2P Channels via a "Finger in the Dam" Mechanism. Cell Chem Biol. 2020 Feb 10. pii: S2451-9456(20)30036-2. doi:, 10.1016/j.chembiol.2020.01.011. PMID:32059793 doi:http://dx.doi.org/10.1016/j.chembiol.2020.01.011

[1]

[2]

[3]

[4]

[5]