Projects per year
Abstract
Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.
Original language | English |
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Pages (from-to) | 323-333 |
Number of pages | 11 |
Journal | Nature Chemical Biology |
Volume | 19 |
Early online date | 3 Nov 2022 |
DOIs | |
Publication status | Published - Mar 2023 |
Keywords
- Chemical genetics
- X-ray crystallography
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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Dive into the research topics of 'Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders'. Together they form a unique fingerprint.Projects
- 3 Finished
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DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/13 → 30/04/18
Project: Research
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A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research
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State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research