Researchers in the laboratory of Professor Alessio Ciulli have designed a small molecule that tricks a particular E3 ubiquitin ligase protein to destroy another of its kind. E3 ligases act like ‘molecular assassins’ in cells as they naturally tag unwanted proteins for cellular degradation. There are believed to be over 600 E3 ligases in the human cell and many are involved in human diseases, providing many attractive targets for drug discovery.
This work, published in Nature Communications today, was conducted primarily by former visiting PhD student (now postdoc) Dr Chiara Maniaci with postdoctoral researchers Dr Scott Hughes and Dr Andrea Testa.
“This small molecule targets one particular E3 ligase protein. It has a tailored ‘two-headed’ design. It brings two molecules of the ‘assassin’ together into a specific orientation that allows them to kill each other,” explained Dr Maniaci. “By acting this way, the small molecule now provides a valuable reagent to complement the arsenal of tools that can be deployed to learn more about what the molecular assassin does inside the cell. To assist in this aim we are planning to include the details on this molecule in the Chemical Probes Portal (http://www.chemicalprobes.org/), an open-access online resource that helps scientists identifying high quality chemical tools for use in biological research and drug discovery. We are also hoping to make the compound freely available via vendor catalogues.”
This discovery furnishes a proof-of-concept for using small molecules as a means to induce an E3 ligase to destroy itself. “The knowledge we have gained from developing our molecule will hopefully inspire further new molecules targeting other E3 ligases to be developed.”
The research was a collaborative project involving researchers from across the School. Amongst the co-authors are Professor Dario Alessi and Professor Sonia Rocha, and the paper also includes contribution from Wengzhan Chan and Dougie Lamont from the Dundee Fingerprints Proteomics Facility.
Photo (from left): Professor Alessio Ciulli, Dr Scott Hughes, Dr Chiara Maniaci and Dr Andrea Testa.