# Identification of the first peptide inhibitor of UBE2C enzymatic activity: insights from metadynamics-guided folding and binding studies

## TL;DR

Scientists designed a peptide that inhibits UBE2C, a cancer-related enzyme, using simulations and experiments to find a new potential cancer therapy.

## Contribution

The first peptide inhibitor of UBE2C enzymatic activity is identified through metadynamics-guided folding and binding studies.

## Key findings

- Peptide 5 binds UBE2C with micromolar affinity and inhibits UBE2C-Ub thioester complex formation.
- Active peptides sample transient β-sheet conformations that correlate with binding compatibility.
- This is the first report of a peptide inhibitor targeting UBE2C enzymatic activity.

## Abstract

UBE2C (also known as UbcH10) is a ubiquitin-conjugating enzyme essential for mitotic progression and a potential therapeutic target in cancer. Here, we report a structure-based design and characterisation of peptides derived from a natural interacting partner (U1) aimed at modulating UBE2C activity. Biophysical and biochemical assays identified peptide 5 as a lead compound, capable of binding UBE2C with micromolar affinity and inhibiting the formation of the UBE2C-Ub thioester complex. Enhanced sampling molecular dynamics simulations revealed that peptide folding landscapes are correlated with activity, with active peptides sampling transient β-sheet conformations compatible with binding. To the best of our knowledge, this is the first report of a peptide inhibitor of UBE2C enzymatic activity.