Scholarlink

<p>The Otopetrin (Otop) proteins, comprising Otop1-3, are proton-gated proton channels with key biological functions. Otop1 acts as a receptor for sour and ammonium salt tastes in mammals, but its gating mechanisms and pharmacology remain poorly understood. Here, we report the functional characterization of three small molecule positive allosteric modulators of Otop1—MFaN, HIMOP, and B2FAMP—that enhance proton gating in a pH-dependent manner, potentiating Otop1 activity under weak acidic but not strong acidic conditions. HIMOP also uniquely enhances Otop1’s alkali gating. These modulators preferentially target Otop1, sparing Otop2 and Otop3, and other ion channels. MFaN activates Otop1 while pr<Emphasis Type="Underline">e</Emphasis>serving its core biophysical and pharmacological properties by associating with key residues on the channel’s S5-6 and S11-12 loops, including a crucial arginine (R554) essential for Zn<sup>2+</sup> and alkali activation. This study identifies important Otop1 modulators and structural elements underlying its gating, paving the way for further exploration of this ion channel.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Preferential allosteric modulation of Otop1 channels by small molecule compounds

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月26日

查看全文
  • Xiangjin Kong,
  • Jie Sun,
  • Hanhan Zhang,
  • Yuan Yin,
  • Xinyao Liang,
  • Yan Chen,
  • Guoqing Luo,
  • Huixin Xia,
  • Youjun Wang,
  • Zhonghua Liu,
  • Cheng Tang

摘要

The Otopetrin (Otop) proteins, comprising Otop1-3, are proton-gated proton channels with key biological functions. Otop1 acts as a receptor for sour and ammonium salt tastes in mammals, but its gating mechanisms and pharmacology remain poorly understood. Here, we report the functional characterization of three small molecule positive allosteric modulators of Otop1—MFaN, HIMOP, and B2FAMP—that enhance proton gating in a pH-dependent manner, potentiating Otop1 activity under weak acidic but not strong acidic conditions. HIMOP also uniquely enhances Otop1’s alkali gating. These modulators preferentially target Otop1, sparing Otop2 and Otop3, and other ion channels. MFaN activates Otop1 while preserving its core biophysical and pharmacological properties by associating with key residues on the channel’s S5-6 and S11-12 loops, including a crucial arginine (R554) essential for Zn2+ and alkali activation. This study identifies important Otop1 modulators and structural elements underlying its gating, paving the way for further exploration of this ion channel.