9e94: Difference between revisions

Latest revision as of 07:10, 11 February 2026

Cryo-EM structure of human TWIK-2 at pH 7.5

Structural highlights

9e94 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.67Å
Ligands:	D10, K
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KCNK6_HUMAN K(+) channel that conducts outward rectifying currents at the membranes of the endolysosomal system (PubMed:10887187, PubMed:28381826). Active in lysosomes where it regulates lysosome numbers and size (PubMed:28381826). In macrophages, enables K(+) efflux coupled to ATP-induced NLRP3 inflammasome activation upon bacterial infection. Cooperates with ATP-gated P2RX7 channels to activate NLRP3 inflammasome, with P2RX7 conducting Ca(2+) and Na(+) influx that sets the membrane potential for K(+) efflux (By similarity).[UniProtKB:Q3TBV4]^[1] ^[2] Does not display channel activity.^[3]

Publication Abstract from PubMed

The Tandem of pore domain in a Weak Inward Rectifying K(+) channel 2 (TWIK-2; KCNK6) is a member of the Two-Pore Domain K(+) (K(2P)) channel family, which is associated with pulmonary hypertension, lung injury, and inflammation. Despite its physiological relevance, the structure, regulatory mechanisms, and selective modulators of TWIK-2 remain largely unknown. Here, we present a 3.7 A single particle cryo-electron microscopy structure of human TWIK-2 and highlight its conserved and distinctive features. Using automated whole-cell patch clamp recordings, we demonstrate that gating in TWIK-2 is voltage-dependent and insensitive to changes in the extracellular pH. We identify key residues that influence TWIK-2 activity by employing site-directed mutagenesis and provide insights into the possible lipid-mediated mechanism of TWIK-2 regulation. Additionally, we demonstrate the application of high-throughput automated whole-cell patch clamp platforms to screen small molecule modulators of TWIK-2. Our work serves as a foundation for designing high-throughput small molecule screening campaigns to identify specific high-affinity TWIK-2 modulators, including promising- anti-inflammatory therapeutics.

Insights into the structure and modulation of human TWIK-2.,Ma Q, Hernandez CC, Navratna V, Kumar A, Rana JK, Zong J, Lee A, Mosalaganti S Nat Commun. 2026 Jan 31. doi: 10.1038/s41467-026-69072-1. PMID:41617707^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, Honoré E. TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem. 2000 Sep 15;275(37):28722-30. PMID:10887187 doi:10.1074/jbc.M003755200
↑ Bobak N, Feliciangeli S, Chen CC, Ben Soussia I, Bittner S, Pagnotta S, Ruck T, Biel M, Wahl-Schott C, Grimm C, Meuth SG, Lesage F. Recombinant tandem of pore-domains in a Weakly Inward rectifying K(+) channel 2 (TWIK2) forms active lysosomal channels. Sci Rep. 2017 Apr 5;7(1):649. PMID:28381826 doi:10.1038/s41598-017-00640-8
↑ Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, Honoré E. TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem. 2000 Sep 15;275(37):28722-30. PMID:10887187 doi:10.1074/jbc.M003755200
↑ Ma Q, Hernandez CC, Navratna V, Kumar A, Rana JK, Zong J, Lee A, Mosalaganti S. Insights into the structure and modulation of human TWIK-2. Nat Commun. 2026 Jan 31. PMID:41617707 doi:10.1038/s41467-026-69072-1

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, Honoré E. TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem. 2000 Sep 15;275(37):28722-30. PMID:10887187 doi:10.1074/jbc.M003755200

[2] Bobak N, Feliciangeli S, Chen CC, Ben Soussia I, Bittner S, Pagnotta S, Ruck T, Biel M, Wahl-Schott C, Grimm C, Meuth SG, Lesage F. Recombinant tandem of pore-domains in a Weakly Inward rectifying K(+) channel 2 (TWIK2) forms active lysosomal channels. Sci Rep. 2017 Apr 5;7(1):649. PMID:28381826 doi:10.1038/s41598-017-00640-8

[3] Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, Honoré E. TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem. 2000 Sep 15;275(37):28722-30. PMID:10887187 doi:10.1074/jbc.M003755200

[4] Ma Q, Hernandez CC, Navratna V, Kumar A, Rana JK, Zong J, Lee A, Mosalaganti S. Insights into the structure and modulation of human TWIK-2. Nat Commun. 2026 Jan 31. PMID:41617707 doi:10.1038/s41467-026-69072-1

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9e94 is ON HOLD  until Paper Publication
+==Cryo-EM structure of human TWIK-2 at pH 7.5==
+<StructureSection load='9e94' size='340' side='right'caption='[[9e94]], [[Resolution|resolution]] 3.67&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9e94]] 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=9E94 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9E94 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.67&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D10:DECANE'>D10</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=9e94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9e94 OCA], [https://pdbe.org/9e94 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9e94 RCSB], [https://www.ebi.ac.uk/pdbsum/9e94 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9e94 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/KCNK6_HUMAN KCNK6_HUMAN] K(+) channel that conducts outward rectifying currents at the membranes of the endolysosomal system (PubMed:10887187, PubMed:28381826). Active in lysosomes where it regulates lysosome numbers and size (PubMed:28381826). In macrophages, enables K(+) efflux coupled to ATP-induced NLRP3 inflammasome activation upon bacterial infection. Cooperates with ATP-gated P2RX7 channels to activate NLRP3 inflammasome, with P2RX7 conducting Ca(2+) and Na(+) influx that sets the membrane potential for K(+) efflux (By similarity).[UniProtKB:Q3TBV4]<ref>PMID:10887187</ref> <ref>PMID:28381826</ref>   Does not display channel activity.<ref>PMID:10887187</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The Tandem of pore domain in a Weak Inward Rectifying K(+) channel 2 (TWIK-2; KCNK6) is a member of the Two-Pore Domain K(+) (K(2P)) channel family, which is associated with pulmonary hypertension, lung injury, and inflammation. Despite its physiological relevance, the structure, regulatory mechanisms, and selective modulators of TWIK-2 remain largely unknown. Here, we present a 3.7 A single particle cryo-electron microscopy structure of human TWIK-2 and highlight its conserved and distinctive features. Using automated whole-cell patch clamp recordings, we demonstrate that gating in TWIK-2 is voltage-dependent and insensitive to changes in the extracellular pH. We identify key residues that influence TWIK-2 activity by employing site-directed mutagenesis and provide insights into the possible lipid-mediated mechanism of TWIK-2 regulation. Additionally, we demonstrate the application of high-throughput automated whole-cell patch clamp platforms to screen small molecule modulators of TWIK-2. Our work serves as a foundation for designing high-throughput small molecule screening campaigns to identify specific high-affinity TWIK-2 modulators, including promising- anti-inflammatory therapeutics.
-Authors:
+Insights into the structure and modulation of human TWIK-2.,Ma Q, Hernandez CC, Navratna V, Kumar A, Rana JK, Zong J, Lee A, Mosalaganti S Nat Commun. 2026 Jan 31. doi: 10.1038/s41467-026-69072-1. PMID:41617707<ref>PMID:41617707</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9e94" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Kumar A]]
+[[Category: Ma Q]]
+[[Category: Mosalaganti S]]
+[[Category: Navratna V]]

9e94: Difference between revisions

Latest revision as of 07:10, 11 February 2026

Cryo-EM structure of human TWIK-2 at pH 7.5

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools