Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

Liu, Yi; Ma, Jichun; DesJarlais, Renee L.; Hagan, Rebecca; Rech, Jason; Lin, David; Liu, Changlu; Miller, Robyn; Schoellerman, Jeffrey; Luo, Jinquan; Letavic, Michael; Grasberger, Bruce; Maher, Michael

doi:10.1038/s42003-021-01678-1

Title: Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

Journal Article · Tue Feb 09 00:00:00 EST 2021 · Communications Biology

DOI:https://doi.org/10.1038/s42003-021-01678-1· OSTI ID:1766154

^[1];

^[2]; DesJarlais, Renee L. ^[2]; Hagan, Rebecca ^[1]; Rech, Jason ^[1]; Lin, David ^[1]; Liu, Changlu ^[1]; Miller, Robyn ^[2]; Schoellerman, Jeffrey ^[1]; Luo, Jinquan ^[2]; Letavic, Michael ^[1]; Grasberger, Bruce ^[2];

^[1]

Janssen Research & Development, L.L.C., San Diego, CA (United States)
Janssen Research & Development, L.L.C., Spring House, PA (United States)

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1766154

Journal Information:: Communications Biology, Vol. 4, Issue 1; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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