8FBL

Human PAC in nanodisc at pH 4.0 with PI(4,5)P2 diC8

This is a non-PDB format compatible entry.

Summary for 8FBL

• Entry DOI: 10.2210/pdb8fbl/pdb
• EMDB information: 28535 28964
• Descriptor: Proton-activated chloride channel, 2-acetamido-2-deoxy-beta-D-glucopyranose, [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate (3 entities in total)
• Functional Keywords: pac, tmem206, asor, paorac, ion channels, chloride channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 102865.06

Authors

Ruan, Z.,Lu, W. (deposition date: 2022-11-29, release date: 2023-02-01)

Primary citation

Mihaljevic, L.,Ruan, Z.,Osei-Owusu, J.,Lu, W.,Qiu, Z.
Inhibition of the proton-activated chloride channel PAC by PIP 2.
Elife, 12:-, 2023

PubMed Abstract: Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by (). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP-binding. Structural and electrophysiological analyses suggest that PIP inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.

PubMed: 36633397
DOI: 10.7554/eLife.83935

Experimental method

ELECTRON MICROSCOPY (2.7 Å)