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-Structure paper
タイトル | Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 6919, Year 2022 |
掲載日 | 2022年11月14日 |
著者 | Xiaolong Gao / Philipp A M Schmidpeter / Vladimir Berka / Ryan J Durham / Chen Fan / Vasanthi Jayaraman / Crina M Nimigean / |
PubMed 要旨 | Understanding how ion channels gate is important for elucidating their physiological roles and targeting them in pathophysiological states. Here, we used SthK, a cyclic nucleotide-modulated channel ...Understanding how ion channels gate is important for elucidating their physiological roles and targeting them in pathophysiological states. Here, we used SthK, a cyclic nucleotide-modulated channel from Spirochaeta thermophila, to define a ligand-gating trajectory that includes multiple on-pathway intermediates. cAMP is a poor partial agonist for SthK and depolarization increases SthK activity. Tuning the energy landscape by gain-of-function mutations in the voltage sensor domain (VSD) allowed us to capture multiple intermediates along the ligand-activation pathway, highlighting the allosteric linkage between VSD, cyclic nucleotide-binding (CNBD) and pore domains. Small, lateral displacements of the VSD S4 segment were necessary to open the intracellular gate, pointing to an inhibitory VSD at rest. We propose that in wild-type SthK, depolarization leads to such VSD displacements resulting in release of inhibition. In summary, we report conformational transitions along the activation pathway that reveal allosteric couplings between key sites integrating to open the intracellular gate. |
リンク | Nat Commun / PubMed:36376326 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.9 - 4.3 Å |
構造データ | EMDB-24670, PDB-7rsh: EMDB-24681, PDB-7rtf: EMDB-24682, PDB-7rtj: EMDB-24692, PDB-7ru0: EMDB-24746, PDB-7ryr: EMDB-24747, PDB-7rys: |
化合物 | ChemComp-CMP: ChemComp-PGW: |
由来 |
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キーワード | TRANSPORT PROTEIN / Cyclic nucleotide-gated ion channel |