Diamond Publications - Search Results

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

One item found (0 items not approved).

Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders Alexander Hanzl , Ryan Casement , Hana Imrichova , Scott J. Hughes , Eleonora Barone , Andrea Testa , Sophie Bauer , Jane Wright , Matthias Brand , Alessio Ciulli , Georg E. Winter Nature Chemical Biology 580 DOI: 10.1038/s41589-022-01177-2 Diamond Proposal Number(s): [14980] Show Abstract ▼ 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.	Nov 2022

Instruments / Technical Area

Publication Details

Published

Actions

I24-Microfocus Macromolecular Crystallography

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders