Structural highlights
FunctionASIC1_CHICK Cation channel with high affinity for sodium, which is gated by extracellular protons and inhibited by the diuretic amiloride (By similarity).[1] Publication Abstract from PubMedAcid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting. Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1.,Liu Y, Ma J, DesJarlais RL, Hagan R, Rech J, Lin D, Liu C, Miller R, Schoellerman J, Luo J, Letavic M, Grasberger B, Maher M Commun Biol. 2021 Feb 9;4(1):174. doi: 10.1038/s42003-021-01678-1. PMID:33564124[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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