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Structure paper

TitleBioactive lipid-mediated structural and functional regulation of the essential human potassium channel Kir7.1.
Journal, issue, pagesNat Commun, Year 2026
Publish dateFeb 11, 2026
AuthorsQingwei Niu / Simon Vu / Yuanjiang Xu / Mingxing Qian / Anastasiia Rudenko / Jin Ye / Jianwei Zeng / Wei Huang / Douglas F Covey / Rui Zhang / Ziao Fu / Polina V Lishko /
PubMed AbstractThe 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- ...The 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 Å to 4.0 Å. These structures uncover the molecular basis of Kir7.1 modulation by PIP, 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 PIP 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.
External linksNat Commun / PubMed:41672996
MethodsEM (single particle)
Resolution3.3 - 4.0 Å
Structure data

EMDB-71798, PDB-9pr5:
Cryo-EM structure of the human inward-rectifier potassium 7.1 channel (Kir7.1) extended state
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-71799, PDB-9pr6:
Cryo-EM structure of the human inward-rectifier potassium 7.1 channel (Kir7.1) docked state
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-71800, PDB-9pr7:
Cryo-EM structure of the human inward-rectifier potassium 7.1 channel (Kir7.1) with enantiomer of 17-hydroxyprogesterone caproate
Method: EM (single particle) / Resolution: 4.0 Å

Chemicals

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-CLR:
CHOLESTEROL

PDB-1cjg:
NMR STRUCTURE OF LAC REPRESSOR HP62-DNA COMPLEX

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / inwardly rectifying potassium channel Kir7.1 / KCNJ13 / electrophysiology / ion channels / steroids / steroid enantiomers

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