9LHJ

UBE2N/UBE2V2 complexed with a covalent inhibitor

This is a non-PDB format compatible entry.

Summary for 9LHJ

• Entry DOI: 10.2210/pdb9lhj/pdb
• Descriptor: Ubiquitin-conjugating enzyme E2 N, Ubiquitin-conjugating enzyme E2 variant 2 (3 entities in total)
• Functional Keywords: covalent inhibitor, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 68125.97

Authors

Li, S.,Wu, X.,Zhou, L.,Lu, X. (deposition date: 2025-01-12, release date: 2025-05-14)

Primary citation

Wu, X.,Li, S.,Liang, T.,Yu, Q.,Zhang, Y.,Liu, J.,Li, K.,Liu, Z.,Cui, M.,Zhao, Y.,Han, X.,Jin, R.,Tan, M.,Chen, X.H.,Zhao, Y.,Zheng, M.,Sun, Y.,Zhou, L.,Lu, X.
Proteome-Wide Data Guides the Discovery of Lysine-Targeting Covalent Inhibitors Using DNA-Encoded Chemical Libraries.
Angew.Chem.Int.Ed.Engl., :e202505581-e202505581, 2025

PubMed Abstract: Broadening the application of covalent inhibitors requires the exploration of nucleophilic residues beyond cysteine. The covalent DNA-encoded chemical library (CoDEL) represents an advanced technology for covalent drug discovery. However, its application in lysine-targeting inhibitors remains uncharted territory. Here, we report the utilization of CoDEL selection guided by proteome-wide data to identify lysine-targeting covalent inhibitors. A comprehensive assessment of activity-based protein profiling (ABPP) data on lysine distribution and ligandability reveals potential targets for selective covalent inhibition, including phosphoglycerate mutase 1 (PGAM1), bromodomain (BRD) family proteins, and ubiquitin-conjugating enzyme E2 N (UBE2N). The 10.7-million-member CoDELs, featuring diverse lysine-reactive warheads, enable the discovery of a series of covalent inhibitors, covering photo-covalent, reversible covalent, and irreversible covalent reaction mechanisms. In-depth characterization of binding sites and modes of action provides structural and functional insights. Notably, irreversible covalent inhibitors unveil a novel mechanism for regulating UBE2N-mediated ubiquitination by modulating the conformation of the protein complex. Our work adopts the ABPP-CoDEL strategy, offering an efficient and versatile selection method for the development of covalent inhibitors targeting functional lysines.

PubMed: 40223230
DOI: 10.1002/anie.202505581

Experimental method

X-RAY DIFFRACTION (1.68 Å)