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bioRxiv · 10.1101/2024.06.07.597981

Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States

Peisley, A.·Hernandez, C. Q.·Dahir, N.·Koepping, L.·Raczkowski, A.·Su, M.·Ghamari-Langroudi, M.·Ji, X.·Gimenez, L.·Cone, R. D.
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Abstract

Hereditary defects in the function of the Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreal degeneration. Studies also suggest that Kir7.1 may be regulated by a GPCR, the melanocortin-4 receptor, in certain hypothalamic neurons. We present the first structures of human Kir7.1 and describe the conformational bias displayed by two pathogenic mutations, R162Q and E276A, to provide an explanation for the basis of disease and illuminate the gating pathway. We also demonstrate the structural basis for the blockade of the channel by a small molecule ML418 and demonstrate that channel blockade in vivo activates MC4R neurons in the paraventricular nucleus of the hypothalamus (PVH), inhibiting food intake and inducing weight loss. Preliminary purification, and structural and pharmacological characterization of an in tandem construct of MC4R and Kir7.1 suggests that the fusion protein forms a homotetrameric channel that retains regulation by liganded MC4R molecules.

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Peisley, A., Hernandez, C. Q., Dahir, N., Koepping, L., Raczkowski, A., Su, M., Ghamari-Langroudi, M., Ji, X., Gimenez, L., Cone, R. D.. 2024-06-08. Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States. https://doi.org/10.1101/2024.06.07.597981

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