9e94
Cryo-EM structure of human TWIK-2 at pH 7.5
Structural highlights
FunctionKCNK6_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 PubMedThe 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
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