Cryo-electron microscopy structures of human Kir7.1 revealed its modulation by PI4,5P2 and identified a steroid-binding site where cholesterol acts as an inhibitor that can be displaced by activating steroids.
High-resolution cryo-EM structures of human Kir7.1 reveal a novel regulatory mechanism where activating steroids displace inhibitory cholesterol to synergize with PIP2, providing a structural basis for developing targeted modulators.
Abstract 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 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.
Niu et al. (Wed,) conducted a other in Kir7.1 channel regulation. Cryo-EM structural analysis and electrophysiology was evaluated on Atomic structure and functional states of Kir7.1. Cryo-electron microscopy structures of human Kir7.1 revealed its modulation by PI4,5P2 and identified a steroid-binding site where cholesterol acts as an inhibitor that can be displaced by activating steroids.