8fbl | pdb_00008fbl
Human PAC in nanodisc at pH 4.0 with PI(4,5)P2 diC8
Structural highlights
FunctionPACC1_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).[1] [2] Publication Abstract from PubMedProton-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. , PMID:36633397[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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