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<p>Posttranslational modifications (PTMs) vastly expand the diversity of the human proteome, dynamically reshaping protein activity, interactions and localization in response to environmental, pharmacologic and disease-associated cues. However, their proteome-wide impact on small-molecule recognition—and, thus, druggability—remains largely unexplored. Here we present a chemical proteomic strategy to delineate how PTM states remodel protein ligandability in human cells. Using broad-spectrum photoaffinity probes, we identified more than 400 functionally diverse proteins whose ability to engage small molecules is impacted by phosphorylation or N-linked glycosylation status. Integrating binding site mapping with structural analyses reveals a diverse array of PTM-dependent pockets. Among these, we discovered that the phosphorylation status of common oncogenic KRAS mutants impacts the action of small molecules, including clinically approved inhibitors. These findings illuminate a previously underappreciated layer of proteome plasticity governed by PTMs and highlight opportunities to develop chemical probes that selectively target proteins in defined modification states.</p><p></p>

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Posttranslational modifications remodel proteome-wide ligandability

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月5日

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  • Weichao Li,
  • Qijia Wei,
  • Manuel Llanos,
  • Clara Gathmann,
  • Paolo Governa,
  • Tzu-Yuan Chiu,
  • Jacob M. Wozniak,
  • Appaso M. Jadhav,
  • Matthew Holcomb,
  • Jacob Cravatt,
  • Ashok Dongre,
  • Mia L. Huang,
  • Stefano Forli,
  • Christopher G. Parker

摘要

Posttranslational modifications (PTMs) vastly expand the diversity of the human proteome, dynamically reshaping protein activity, interactions and localization in response to environmental, pharmacologic and disease-associated cues. However, their proteome-wide impact on small-molecule recognition—and, thus, druggability—remains largely unexplored. Here we present a chemical proteomic strategy to delineate how PTM states remodel protein ligandability in human cells. Using broad-spectrum photoaffinity probes, we identified more than 400 functionally diverse proteins whose ability to engage small molecules is impacted by phosphorylation or N-linked glycosylation status. Integrating binding site mapping with structural analyses reveals a diverse array of PTM-dependent pockets. Among these, we discovered that the phosphorylation status of common oncogenic KRAS mutants impacts the action of small molecules, including clinically approved inhibitors. These findings illuminate a previously underappreciated layer of proteome plasticity governed by PTMs and highlight opportunities to develop chemical probes that selectively target proteins in defined modification states.