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Related Experiment Video

Updated: May 25, 2025

In Vitro Analysis of E3 Ubiquitin Ligase Function

In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

Molecular glue-augmented E2-ubiquitin recognition from a computational approach.

Danial Muhammad¹, Wei Xia², Musheng Wang¹

¹Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen 518107, China; Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.

International Journal of Biological Macromolecules

|February 27, 2025

Summary

A new computational method accurately predicts molecular glue interactions with ubiquitin-E2 complexes, aiding in the discovery of new drugs for protein degradation. This advances understanding of ubiquitination and protein binding.

Keywords:

Cooperativity Molecular glue Protein-ligand binding Protein-protein interaction Ubiquitin

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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta

Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta

Published on: December 5, 2019

Area of Science:

Computational Chemistry
Biochemistry
Structural Biology

Background:

Ubiquitin (Ub) targets misfolded proteins for proteasomal degradation.
Molecular glues (MGs) enhance protein-protein interactions, particularly in ubiquitination.
Efficient computational methods for studying MG-Ub-protease systems are lacking.

Purpose of the Study:

To introduce a cost-effective computational framework for characterizing the thermodynamics of molecular glue-induced ubiquitination.
To analyze the thermodynamics of Ub-E2 recognition enhancement by MGs.
To facilitate high-throughput virtual screening of MGs for protein-protein recognition.

Main Methods:

Developed an all-atom computational framework to analyze thermodynamic driving forces.
Tested the framework on the CDC34A-Ub system with 18 different molecular glues.
Compared the method with standard approaches like MM/GBSA and AutoDock Vina.

Main Results:

The framework successfully decoded interaction thermodynamics in the multimeric system.
It enabled ranking of molecular glue-E2-Ub affinities and captured MG-induced interaction strengthening.
Identified key interfacial residues involved in molecular glue and Ub-E2 binding.

Conclusions:

The developed computational approach accurately characterizes molecular glue-protein interactions.
It outperforms standard methods in analyzing complex ubiquitination systems.
This framework can accelerate the discovery of novel molecular glues for therapeutic applications.