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Related Experiment Video

Updated: Sep 12, 2025

Simultaneous Affinity Enrichment of Two Post-Translational Modifications for Quantification and Site Localization

Simultaneous Affinity Enrichment of Two Post-Translational Modifications for Quantification and Site Localization

Published on: February 27, 2020

Post-Translational Modifications Remodel Proteome-Wide Ligandability.

Weichao Li, Qijia Wei, Paolo Governa

Biorxiv : the Preprint Server for Biology

|August 6, 2025

Summary

Post-translational modifications (PTMs) reshape protein function and druggability. This study reveals how phosphorylation and glycosylation impact protein-ligand interactions, identifying new therapeutic targets.

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Last Updated: Sep 12, 2025

Simultaneous Affinity Enrichment of Two Post-Translational Modifications for Quantification and Site Localization

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Published on: February 27, 2020

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations

Profiling Ubiquitin and Ubiquitin-like Dependent Post-translational Modifications and Identification of Significant Alterations

Published on: November 7, 2019

Utilizing a Comprehensive Immunoprecipitation Enrichment System to Identify an Endogenous Post-translational Modification Profile for Target Proteins

Published on: January 8, 2018

Area of Science:

Biochemistry
Chemical Biology
Proteomics

Background:

Post-translational modifications (PTMs) significantly expand proteome diversity, influencing protein activity, interactions, and localization.
While PTMs' effects on protein function are known, their proteome-wide impact on small-molecule recognition and druggability is poorly understood.

Purpose of the Study:

To investigate how PTM states remodel protein ligandability across the human proteome.
To identify proteins whose small-molecule binding is modulated by phosphorylation or N-linked glycosylation.

Main Methods:

Utilized a chemical proteomic strategy with broad-profiling photoaffinity probes.
Integrated binding site mapping and structural analyses to identify PTM-dependent pockets.
Examined the impact of phosphorylation on oncogenic KRAS mutants and their interaction with small molecules.

Main Results:

Identified over 400 diverse proteins whose small-molecule engagement is affected by phosphorylation or N-linked glycosylation.
Discovered various PTM-dependent binding pockets through structural analysis.
Found that KRAS phosphorylation status influences the efficacy of small-molecule inhibitors.

Conclusions:

PTMs represent a critical, underappreciated layer of proteome plasticity governing ligandability.
This work uncovers opportunities for developing chemical probes targeting proteins in specific modification states.
Understanding PTM-dependent druggability can advance targeted therapies.