Scholarlink

<p>Despite the crucial biological functions of arginine, its reactivity and ligandability within the human proteome remain largely unexplored. Here we apply activity-based protein profiling (ABPP) with phenylglyoxal-based chemical probes to map arginine reactivity globally. Screening phenylglyoxal derivatives identified a probe with enhanced coverage and selectivity, enabling quantification of 4,606 arginine sites across human cell lines. Among these, critical residues regulate liquid–liquid phase separation. Arginine reactivity was further assessed by on-beads reductive dimethylation proteomics, revealing a subset of hyper-reactive sites. Competitive fragment screening using data-independent acquisition ABPP (DIA-ABPP) generated a ligandability map of arginine residues across 60 dicarbonyl compounds. This dataset revealed ligandable arginines that modulate protein activity, in particular protein–protein interactions, highlighting potential covalent drug targets. Together, this work provides a proteome-wide profile of arginine reactivity and ligandability, offering insights into the functional landscape of arginines and expanding the scope of covalent drug discovery to include arginine-targeting molecules.</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

Global profiling of arginine reactivity and ligandability in the human proteome

  • 期刊论文

  • 发表日期：

    2026年1月2日

查看全文
  • Yuena Wang,
  • Tao Hu,
  • Lin Zhu,
  • Shaoshuai Xie,
  • Xi Yang,
  • Caifeng Xu,
  • Yansheng Zhai,
  • Youming Li,
  • Xiaoyan Huang,
  • Bo Yang,
  • Gang Li

摘要

Despite the crucial biological functions of arginine, its reactivity and ligandability within the human proteome remain largely unexplored. Here we apply activity-based protein profiling (ABPP) with phenylglyoxal-based chemical probes to map arginine reactivity globally. Screening phenylglyoxal derivatives identified a probe with enhanced coverage and selectivity, enabling quantification of 4,606 arginine sites across human cell lines. Among these, critical residues regulate liquid–liquid phase separation. Arginine reactivity was further assessed by on-beads reductive dimethylation proteomics, revealing a subset of hyper-reactive sites. Competitive fragment screening using data-independent acquisition ABPP (DIA-ABPP) generated a ligandability map of arginine residues across 60 dicarbonyl compounds. This dataset revealed ligandable arginines that modulate protein activity, in particular protein–protein interactions, highlighting potential covalent drug targets. Together, this work provides a proteome-wide profile of arginine reactivity and ligandability, offering insights into the functional landscape of arginines and expanding the scope of covalent drug discovery to include arginine-targeting molecules.