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-Structure paper
タイトル | The inhibition mechanism of the SUR2A-containing K channel by a regulatory helix. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 3608, Year 2023 |
掲載日 | 2023年6月17日 |
著者 | Dian Ding / Tianyi Hou / Miao Wei / Jing-Xiang Wu / Lei Chen / |
PubMed 要旨 | K 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 ...K 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 K 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. |
リンク | Nat Commun / PubMed:37330603 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.0 - 3.8 Å |
構造データ | EMDB-33563, PDB-7y1j: EMDB-33564, PDB-7y1k: EMDB-33565, PDB-7y1l: EMDB-33566, PDB-7y1m: EMDB-33567, PDB-7y1n: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-BJX: ChemComp-ADP: |
由来 |
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キーワード | MEMBRANE PROTEIN / SUR2A / ABC transporter / repaglinide / SUR2B |