Identification of the first peptide inhibitor of UBE2C enzymatic activity: insights from metadynamics-guided folding and binding studies
Luciano Pirone, Bianca Fiorillo, Annarita Del Gatto, Rita Russo, Alessandra Guarracino, Chiara Cassiano, Laura Zaccaro, Federica Moraca, Emilia Pedone, Bruno Catalanotti
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.
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.
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Taxonomy
TopicsUbiquitin and proteasome pathways · Protein Degradation and Inhibitors · Microtubule and mitosis dynamics