7ZNT

CRYSTAL STRUCTURE OF AT7 IN COMPLEX WITH THE SECOND BROMODOMAIN OF HUMAN BRD4 AND PVHL:ELONGINC:ELONGINB

Summary for 7ZNT

• Entry DOI: 10.2210/pdb7znt/pdb
• Descriptor: Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (6 entities in total)
• Functional Keywords: protac ternary complex, e3 ligase, protac, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 115004.70

Authors

Hughes, S.J.,Casement, R.,Ciulli, A. (deposition date: 2022-04-22, release date: 2022-09-14, Last modification date: 2024-02-07)

Primary citation

Hanzl, A.,Casement, R.,Imrichova, H.,Hughes, S.J.,Barone, E.,Testa, A.,Bauer, S.,Wright, J.,Brand, M.,Ciulli, A.,Winter, G.E.
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.
Nat.Chem.Biol., 19:323-333, 2023

PubMed 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.

PubMed: 36329119
DOI: 10.1038/s41589-022-01177-2

Experimental method

X-RAY DIFFRACTION (3 Å)