6WBN

Cryo-EM structure of human Pannexin 1 channel N255A mutant, gap junction

Summary for 6WBN

• Entry DOI: 10.2210/pdb6wbn/pdb
• EMDB information: 21588 21589 21590 21591 21592 21593 21594 21595 21596 21597 21598
• Descriptor: Pannexin-1, PHOSPHATIDYLETHANOLAMINE, 1,2-Distearoyl-sn-glycerophosphoethanolamine, ... (5 entities in total)
• Functional Keywords: ion channel, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 14
• Total formula weight: 641464.42

Authors

Lu, W.,Du, J.,Ruan, Z. (deposition date: 2020-03-26, release date: 2020-06-03, Last modification date: 2024-10-16)

Primary citation

Ruan, Z.,Orozco, I.J.,Du, J.,Lu, W.
Structures of human pannexin 1 reveal ion pathways and mechanism of gating.
Nature, 584:646-651, 2020

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. 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.

PubMed: 32494015
DOI: 10.1038/s41586-020-2357-y

Experimental method

ELECTRON MICROSCOPY (2.83 Å)