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-Structure paper
タイトル | Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations. |
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ジャーナル・号・ページ | Life Sci Alliance, Vol. 4, Issue 8, Year 2021 |
掲載日 | 2021年7月1日 |
著者 | Urška Rovšnik / Yuxuan Zhuang / Björn O Forsberg / Marta Carroni / Linnea Yvonnesdotter / Rebecca J Howard / Erik Lindahl / |
PubMed 要旨 | Ligand-gated ion channels are critical mediators of electrochemical signal transduction across evolution. Biophysical and pharmacological characterization of these receptor proteins relies on high- ...Ligand-gated ion channels are critical mediators of electrochemical signal transduction across evolution. Biophysical and pharmacological characterization of these receptor proteins relies on high-quality structures in multiple, subtly distinct functional states. However, structural data in this family remain limited, particularly for resting and intermediate states on the activation pathway. Here, we report cryo-electron microscopy (cryo-EM) structures of the proton-activated ligand-gated ion channel (GLIC) under three pH conditions. Decreased pH was associated with improved resolution and side chain rearrangements at the subunit/domain interface, particularly involving functionally important residues in the β1-β2 and M2-M3 loops. Molecular dynamics simulations substantiated flexibility in the closed-channel extracellular domains relative to the transmembrane ones and supported electrostatic remodeling around E35 and E243 in proton-induced gating. Exploration of secondary cryo-EM classes further indicated a low-pH population with an expanded pore. These results allow us to define distinct protonation and activation steps in pH-stimulated conformational cycling in GLIC, including interfacial rearrangements largely conserved in the pentameric channel family. |
リンク | Life Sci Alliance / PubMed:34210687 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.4 - 4.1 Å |
構造データ | EMDB-11202, PDB-6zgd: EMDB-11208, PDB-6zgj: EMDB-11209, PDB-6zgk: EMDB-12675: EMDB-12677: EMDB-12678: |
由来 |
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キーワード | MEMBRANE PROTEIN / GLIC / pentameric ligand-gated ion channel / cryoem |