Neuroscience Discovery, Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, USA.
Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, P.O. Box 776, Spring House, PA, 19477, USA.
Commun Biol. 2021 Feb 9;4(1):174. doi: 10.1038/s42003-021-01678-1.
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.
酸敏离子通道 (ASICs) 是质子门控阳离子通道，对神经元功能至关重要。主要的 ASIC 同工型和质子传感器 ASIC1 的研究表明，富含酸性残基的细胞外区域酸性口袋是门控的关键参与者。虽然毒液肽 psalmotoxin 与该区域的结合调节了通道门控，但小分子对 ASIC 门控调节的分子和结构机制仍知之甚少。在这里，我们结合功能、晶体学、计算和突变方法，表明两种结构上不同的小分子通过结合酸性口袋并稳定大鼠/鸡 ASIC1 的关闭状态，有力且变构地抑制通道的激活和脱敏。我们的工作确定了一个以前未被识别的结合位点，阐明了小分子调节 ASIC 门控的分子机制，并直接证明了这种调节的结构基础，为 ASIC 门控、调节和治疗靶向提供了机制和结构见解。
