8fbl

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

spinqualitylabelsall models 8fbl, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fbl is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.7Å Ligands: NAG, PIO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PACC1_HUMAN Proton-activated chloride channel that mediates import of chloride ion in response to extracellular acidic pH (PubMed:31023925, PubMed:31318332). Involved in acidosis-induced cell death by mediating chloride influx and subsequent cell swelling (PubMed:31023925, PubMed:31318332). Publication Abstract from PubMed Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 (TMEM206). 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(2)) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP(2) 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(2)-binding. Structural and electrophysiological analyses suggest that PIP(2) inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP(2) as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel. Inhibition of the proton-activated chloride channel PAC by PIP(2).,Mihaljevic L, Ruan Z, Osei-Owusu J, Lu W, Qiu Z Elife. 2023 Jan 12;12:e83935. doi: 10.7554/eLife.83935. PMID:36633397 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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