The inwardly rectifying potassium channel Kir7.1 is essential for the physiological function of diverse tissues, including the retinal pigment epithelium and 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 PI4,5P2 and identify a previously unrecognized steroid-binding site that may mediate cooperative channel gating. Our data suggest that endogenous cholesterol acts as an inhibitory ligand, which can be displaced by select activating steroids. These activating steroids work in concert with PI4,5P2 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 novel tools to probe and modulate channel function in both physiological and pathological contexts.
Qingwei Niu (Sun,) studied this question.