9pr7
Cryo-EM structure of the human inward-rectifier potassium 7.1 channel (Kir7.1) with enantiomer of 17-hydroxyprogesterone caproate
Structural highlights
DiseaseKCJ13_HUMAN Leber congenital amaurosis;Snowflake vitreoretinal degeneration. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionKCJ13_HUMAN Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ13 has a very low single channel conductance, low sensitivity to block by external barium and cesium, and no dependence of its inward rectification properties on the internal blocking particle magnesium.[1] [2] Publication Abstract from PubMedThe inwardly rectifying potassium channel Kir7.1 is essential for the physiological function of diverse tissues, including the retinal pigment epithelium and the gestational myometrium. Loss-of-function mutations in KCNJ13, which encodes Kir7.1, or conditional ablation of Kir7.1 in the retinal pigment epithelium, lead to early-onset vision loss. Despite strong genetic evidence supporting Kir7.1 as a therapeutic target, its regulation by endogenous ligands-beyond phosphoinositides-remains poorly understood. Here, we report cryo-electron microscopy structures of human Kir7.1 in multiple functional states at resolutions ranging from 2.8 A to 4.0 A. These structures uncover the molecular basis of Kir7.1 modulation by PI(4,5)P(2), its selectivity, rectification, and identify a distinct steroid-binding site that may mediate cooperative channel gating. Our data suggest that endogenous cholesterol acts as an inhibitory ligand, which is displaced by select activating steroids. These activating steroids work in concert with PI(4,5)P(2) to promote channel opening through profound changes in cytoplasmic domains, and the linker region. Electrophysiological analyses define a pharmacological landscape of Kir7.1 activators, providing innovative tools to probe and modulate channel function in both physiological and pathological contexts. Bioactive lipid-mediated structural and functional regulation of the essential human potassium channel Kir7.1.,Niu Q, Vu S, Xu Y, Qian M, Rudenko A, Ye J, Zeng J, Huang W, Covey DF, Zhang R, Fu Z, Lishko PV Nat Commun. 2026 Feb 11. doi: 10.1038/s41467-026-68819-0. PMID:41672996[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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