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

Dian Ding, Tianyi Hou, Miao Wei, Jing-Xiang Wu, Lei Chen

Nature communications 2023 Jun 17

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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. © 2023. The Author(s).

Citation

Dian Ding, Tianyi Hou, Miao Wei, Jing-Xiang Wu, Lei Chen. The inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix. Nature communications. 2023 Jun 17;14(1):3608