POSTPONED: How PROTAC degraders work: Molecular recognition and design principles Professor Alessio Ciulli (University of Dundee) presents his work on protein-protein interactions and protein degradation to discover novel therapeutics. Hosted by Dr Bill Grey.

Seminar
This event has now finished.
  • Date and time: Friday 16 February 2024, 1pm to 2pm
  • Location: Dianna Bowles Lecture Theatre, B/K/018, Biology Building, Campus West, University of York (Map)
  • Audience: Open to alumni, staff, students (postgraduate researchers, taught postgraduates, undergraduates)
  • Admission: Free admission, booking not required

Event details

THIS SEMINAR HAS BEEN POSTPONED - NEW DATE TBA

 

Abstract

Our laboratory uses molecular information on protein-protein interactions and protein degradation to discover novel therapeutics. Degrader molecules, also known as PROTACs (PROteolysis-Targeting Chimeras) recruit proteins to E3 ligases for targeted protein degradation. Formation of a ternary complex between the PROTAC, the E3 and the target leads to the tagging of the target protein by ubiquitination, and subsequent proteasomal degradation. In cancer, one such drug target is the E3 ubiquitin ligase VHL, which can be hijacked by PROTACs. Our lab solved crystal structures of VHL bound to fragments of its natural substrate and analysed it to design and synthesize novel small molecule ligands  of VHL. We tethered the VHL ligand to a small molecule inhibitor targeting BRD4, a protein frequently deregulated in leukemia. The resulting PROTAC MZ1 bridges BRD4 with VHL and removes BRD4 from leukemic cells. Solving the structure of the ternary bridging complex, we unravelled how the PROTAC MZ1 glue BRD4 to VHL, illuminating structural and biophysical insights into PROTAC molecular recognition and mechanism of action. This fundamental understanding has enabled us to develop further small molecules for hard to target proteins and shown how to improve PROTAC activity.

About the speaker

Professor Alessio Ciulli

Alessio Ciulli holds the Personal Chair of Chemical Structural Biology at the School of Life Sciences, University of Dundee. Alessio studied chemistry in Florence, Italy, and obtained his PhD from the University of Cambridge, UK, in 2006. After postdoctoral research in Cambridge and a brief visit at Yale University in the USA, he returned to Cambridge in 2009 to start his independent laboratory. In 2013, he moved to the University of Dundee, UK, where he was promoted to full professor in 2016. He has received numerous awards, including most recently the Prous Institute – Overton and Meyer Award for New Technologies in Drug Discovery. He is the scientific founder of Amphista therapeutics, a targeted protein degradation company spin out of his laboratory, and the founder of the University of Dundee’s new Centre for Targeted Protein Degradation which he directs and opened in January 2023.