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-Structure paper
タイトル | Structures of human pannexin 1 reveal ion pathways and mechanism of gating. |
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ジャーナル・号・ページ | Nature, Vol. 584, Issue 7822, Page 646-651, Year 2020 |
掲載日 | 2020年6月3日 |
著者 | Zheng Ruan / Ian J Orozco / Juan Du / Wei Lü / |
PubMed 要旨 | Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation, apoptotic cell clearance and human oocyte development. ...Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation, apoptotic cell clearance and human oocyte development. Here we present several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 angström, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating mechanism that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone-binding site embraced by W74 in the extracellular entrance and a role for carbenoxolone as a channel blocker. We identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provide a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels. |
リンク | Nature / PubMed:32494015 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.83 - 6.04 Å |
構造データ | EMDB-21588, PDB-6wbf: EMDB-21589, PDB-6wbg: EMDB-21590, PDB-6wbi: EMDB-21591, PDB-6wbk: EMDB-21592, PDB-6wbl: EMDB-21593, PDB-6wbm: EMDB-21594, PDB-6wbn: EMDB-21595: EMDB-21596: EMDB-21597: EMDB-21598: |
化合物 | ChemComp-PTY: ChemComp-3PE: ChemComp-DGA: ChemComp-CLR: ChemComp-NAG: ChemComp-CBO: |
由来 |
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キーワード | TRANSPORT PROTEIN / ion channel |