Posttranslational modifications remodel proteome-wide ligandability

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.