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TitleInsights into the structure and modulation of human TWIK-2.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJan 31, 2026
AuthorsQianqian Ma / Ciria C Hernandez / Vikas Navratna / Arvind Kumar / Jaimin K Rana / Jiameng Zong / Abraham Lee / Shyamal Mosalaganti /
PubMed AbstractThe 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) channel family, which is associated with pulmonary hypertension, lung ...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) 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 Å 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.
External linksNat Commun / PubMed:41617707
MethodsEM (single particle)
Resolution3.67 Å
Structure data

47768

9e94

EMDB-47768, PDB-9e94:
Cryo-EM structure of human TWIK-2 at pH 7.5
Method: EM (single particle) / Resolution: 3.67 Å

Chemicals

ChemComp-D10:
DECANE

ChemComp-K:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Potassium ion channel K2P

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