Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Year: 2022
Type: article
Abstract: Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. Based on the structure of the degrader and the neosubstrate, different E3 ligase interfaces are critically involved in this process, thus forming defined “functional hotspots”. Understanding disruptive mutations in functional hotspots informs on the architecture of the underlying assembly, and highlights residues prone to cause drug resistance. Until now, their identification was driven by structural methods with limited scalability. Here, we employ haploid genetics to show that hotspot mutations cluster in the substrate receptors of the hijacked ligases and find that type and frequency of mutations are shaped by the essentiality of the harnessed ligase. Intersection with deep mutational scanning data revealed hotspots that are either conserved, or specific for chemically distinct degraders or recruited neosubstrates. Biophysical and structural validation suggest that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we identified and validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and experimentally widely accessible methodology that empowers the characterization of small-molecule degraders and informs on associated resistance mechanisms.
Source: Nature Chemical Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Awards: East of Scotland Bioscience Doctoral Training Partnership, G119964413, G1252602067, A Translational Engine for Biomedical Discoveries ., G2551845503, G2649151654, Chemical Dissection of the Super Elongation Complex, G3207356259, G3468372981, G393177772, G4134516304, Development of c-RAF degraders to probe KRAS mutant cancers, G434337789, State-of-the-art facilities for structural biology at the University of Dundee., State-of-the-art facilities for structural biology at the University of Dundee., G5702163051, G6425946098, G7430948070, G7805879211, G802116698, A Translational Engine for Biomedical Discoveries ., G8992713555
OpenAlex ID: W4308099893