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Covalently Linked Protein Regulators02:04

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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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Simultaneous Affinity Enrichment of Two Post-Translational Modifications for Quantification and Site Localization
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Posttranslational modifications remodel proteome-wide ligandability.

Weichao Li1, Qijia Wei1,2, Manuel Llanos3

  • 1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Nature Chemical Biology
|May 5, 2026
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Summary
This summary is machine-generated.

Posttranslational modifications (PTMs) change how proteins interact with drugs. This study reveals how PTMs impact protein druggability, offering new ways to target diseases.

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Area of Science:

  • Biochemistry
  • Chemical Biology
  • Proteomics

Background:

  • Posttranslational modifications (PTMs) significantly increase proteome diversity.
  • The impact of PTMs on small-molecule recognition and druggability is largely unknown.
  • Understanding PTMs is crucial for drug discovery and development.

Purpose of the Study:

  • To investigate how PTM states influence protein ligandability across the human proteome.
  • To identify proteins whose small-molecule binding is modulated by phosphorylation or N-linked glycosylation.
  • To explore the structural basis of PTM-dependent small-molecule recognition.

Main Methods:

  • Utilized a chemical proteomic strategy employing broad-spectrum photoaffinity probes.
  • Identified over 400 proteins affected by phosphorylation or N-linked glycosylation in their small-molecule interactions.
  • Integrated binding site mapping and structural analyses to characterize PTM-dependent pockets.

Main Results:

  • Discovered that phosphorylation status of KRAS mutants affects small-molecule inhibitor efficacy.
  • Revealed diverse PTM-dependent binding pockets across numerous proteins.
  • Demonstrated that PTMs significantly remodel protein ligandability.

Conclusions:

  • PTMs represent a critical layer of proteome plasticity impacting druggability.
  • Targeting proteins in specific modification states offers new therapeutic opportunities.
  • Developed a method to identify PTM-modulated protein-ligand interactions for drug discovery.