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-Structure paper
Title | Structures of human pannexin 1 reveal ion pathways and mechanism of gating. |
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Journal, issue, pages | Nature, Vol. 584, Issue 7822, Page 646-651, Year 2020 |
Publish date | Jun 3, 2020 |
![]() | Zheng Ruan / Ian J Orozco / Juan Du / Wei Lü / ![]() |
PubMed Abstract | 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. |
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Methods | EM (single particle) |
Resolution | 2.83 - 6.04 Å |
Structure data | 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: |
Chemicals | ![]() ChemComp-PTY: ![]() ChemComp-3PE: ![]() ChemComp-DGA: ![]() ChemComp-CLR: ![]() ChemComp-NAG: ![]() ChemComp-CBO: |
Source |
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![]() | TRANSPORT PROTEIN / ion channel |