The inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix

Dian Ding, Tianyi Hou, Miao Wei, Jing-Xiang Wu and Lei Chen ()
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Dian Ding: Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Tianyi Hou: Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Miao Wei: Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Jing-Xiang Wu: Beijing Key Laboratory of Cardiometabolic Molecular Medicine
Lei Chen: Beijing Key Laboratory of Cardiometabolic Molecular Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract KATP channels are metabolic sensors for intracellular ATP/ADP ratios, play essential roles in many physiological processes, and are implicated in a spectrum of pathological conditions. SUR2A-containing KATP channels differ from other subtypes in their sensitivity to Mg-ADP activation. However, the underlying structural mechanism remains poorly understood. Here we present a series of cryo-EM structures of SUR2A in the presence of different combinations of Mg-nucleotides and the allosteric inhibitor repaglinide. These structures uncover regulatory helix (R helix) on the NBD1-TMD2 linker, which wedges between NBD1 and NBD2. R helix stabilizes SUR2A in the NBD-separated conformation to inhibit channel activation. The competitive binding of Mg-ADP with Mg-ATP to NBD2 mobilizes the R helix to relieve such inhibition, allowing channel activation. The structures of SUR2B in similar conditions suggest that the C-terminal 42 residues of SUR2B enhance the structural dynamics of NBD2 and facilitate the dissociation of the R helix and the binding of Mg-ADP to NBD2, promoting NBD dimerization and subsequent channel activation.

Date: 2023
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DOI: 10.1038/s41467-023-39379-4

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