6X9H

Molecular mechanism and structural basis of small-molecule modulation of acid-sensing ion channel 1 (ASIC1)

Summary for 6X9H

• Entry DOI: 10.2210/pdb6x9h/pdb
• Descriptor: Acid-sensing ion channel 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[4-(3,4-dimethoxyphenoxy)phenyl]-1H-benzimidazole-6-carboximidamide, ... (4 entities in total)
• Functional Keywords: asic1, modulation, membrane protein, transport protein
• Biological source: Gallus gallus (Chicken)
• Total number of polymer chains: 3
• Total formula weight: 152314.13

Authors

Liu, Y.,Ma, J.,DesJarlais, R.L.,Hagan, R.,Rech, J.,Lin, D.,Liu, C.,Miller, R.,Schoellerman, J.,Luo, J.,Letavic, M.,Grasberger, B.,Maher, M. (deposition date: 2020-06-02, release date: 2020-12-30, Last modification date: 2024-11-13)

Primary citation

Liu, Y.,Ma, J.,DesJarlais, R.L.,Hagan, R.,Rech, J.,Lin, D.,Liu, C.,Miller, R.,Schoellerman, J.,Luo, J.,Letavic, M.,Grasberger, B.,Maher, M.
Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1.
Commun Biol, 4:174-174, 2021

PubMed Abstract: Acid-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.

PubMed: 33564124
DOI: 10.1038/s42003-021-01678-1

Experimental method

X-RAY DIFFRACTION (3.01 Å)