EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism.
ジャーナル・号・ページ	Elife, Vol. 12, Year 2024
掲載日	2024年2月12日
著者	Mengyuan Xu / Torben Neelands / Alexander S Powers / Yan Liu / Steven D Miller / Grigore D Pintilie / J Du Bois / Ron O Dror / Wah Chiu / Merritt Maduke /
PubMed 要旨	CLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different tissues. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated ...CLC-2 is a voltage-gated chloride channel that contributes to electrical excitability and ion homeostasis in many different tissues. Among the nine mammalian CLC homologs, CLC-2 is uniquely activated by hyperpolarization, rather than depolarization, of the plasma membrane. The molecular basis for the divergence in polarity of voltage gating among closely related homologs has been a long-standing mystery, in part because few CLC channel structures are available. Here, we report cryoEM structures of human CLC-2 at 2.46 - 2.76 Å, in the presence and absence of the selective inhibitor AK-42. AK-42 binds within the extracellular entryway of the Cl-permeation pathway, occupying a pocket previously proposed through computational docking studies. In the apo structure, we observed two distinct conformations involving rotation of one of the cytoplasmic C-terminal domains (CTDs). In the absence of CTD rotation, an intracellular N-terminal 15-residue hairpin peptide nestles against the TM domain to physically occlude the Cl-permeation pathway. This peptide is highly conserved among species variants of CLC-2 but is not present in other CLC homologs. Previous studies suggested that the N-terminal domain of CLC-2 influences channel properties via a "ball-and-chain" gating mechanism, but conflicting data cast doubt on such a mechanism, and thus the structure of the N-terminal domain and its interaction with the channel has been uncertain. Through electrophysiological studies of an N-terminal deletion mutant lacking the 15-residue hairpin peptide, we support a model in which the N-terminal hairpin of CLC-2 stabilizes a closed state of the channel by blocking the cytoplasmic Cl-permeation pathway.
リンク	Elife / PubMed:38345841 / PubMed Central
手法	EM (単粒子)
解像度	2.46 - 4.03 Å
構造データ	41126 8ta2 EMDB-41126, PDB-8ta2: Cryo-EM structure of the human CLC-2 chloride channel transmembrane domain with bound inhibitor AK-42 手法: EM (単粒子) / 解像度: 2.74 Å 41127 8ta3 EMDB-41127, PDB-8ta3: Cryo-EM structure of the human CLC-2 chloride channel transmembrane domain Apo state with resolved N-terminal hairpin 手法: EM (単粒子) / 解像度: 2.46 Å 41128 8ta4 EMDB-41128, PDB-8ta4: Cryo-EM structure of the human CLC-2 chloride channel transmembrane domain with symmetric C-terminal 手法: EM (単粒子) / 解像度: 2.75 Å 41129 8ta5 EMDB-41129, PDB-8ta5: Title: Cryo-EM structure of the human CLC-2 chloride channel transmembrane domain with asymmetric C-terminal 手法: EM (単粒子) / 解像度: 2.76 Å 41130 8ta6 EMDB-41130, PDB-8ta6: Cryo-EM structure of the human CLC-2 chloride channel C-terminal domain 手法: EM (単粒子) / 解像度: 4.03 Å
化合物	ChemComp-GH6: 2-[[2,6-bis(chloranyl)-3-phenylmethoxy-phenyl]amino]pyridine-3-carboxylic acid ChemComp-CL: Unknown entry / クロリド
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN/INHIBITOR / Chloride / Channel / Inhibitor / Protein / Voltage gated / TRANSPORT PROTEIN-INHIBITOR complex / TRANSPORT PROTEIN