9PG9

Structure of UBR2-AF27 complex

This is a non-PDB format compatible entry.

Summary for 9PG9

• Entry DOI: 10.2210/pdb9pg9/pdb
• Related: 9PG4
• Related PRD ID: PRD_002579
• Descriptor: E3 ubiquitin-protein ligase UBR2, AF27 peptide, ZINC ION, ... (4 entities in total)
• Functional Keywords: ubr, e3 ligase, peptidomimetics ligands, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 17910.28

Authors

Huang, S.,Wu, J.,Taylor, S.,Chen, Y. (deposition date: 2025-07-07, release date: 2026-05-20)

Primary citation

Huang, S.T.,Faouzi, A.,Thomas, N.,Wu, J.,Pestonjamasp, K.,Chen, D.H.,Ren, T.,Kuang, Y.,Taylor, S.,Chen, Y.
Development of High-Affinity Ligands for Human UBR2.
J.Med.Chem., 2026

PubMed Abstract: UBR box-containing ubiquitin E3 ligases recognize the N-termini of their target proteins through the UBR box, and a member of the family, UBR2, has been established as a target to treat cancer- and diabetes-associated cachexia. However, the development of high-affinity small-molecule ligands for UBR2 has not been reported. We developed high-affinity UBR2 ligands through a peptidomimetic approach by incorporating unnatural amino acids to obtain ligands that bind to UBR2 with ∼ 20-40 nM and with 10-fold selectivity over UBR2's closest homologue, UBR1. High-resolution cocrystal structures (∼1.2 Å) of UBR2 in complexes with two high-affinity tripeptides revealed molecular mechanisms for their high-affinity binding. Importantly, a high-affinity UBR2 ligand effectively attenuated cancer-induced cachexia in a cellular model. Our findings demonstrate that the UBR boxes are ligandable and thus could spur interest in targeting this class of E3 ligases for developing novel therapeutic approaches for the treatment of cachexia and other illnesses.

PubMed: 42102356
DOI: 10.1021/acs.jmedchem.5c02881

Experimental method

X-RAY DIFFRACTION (1.22 Å)