9DNQ

Structure of UBR2-RYF complex

Summary for 9DNQ

• Entry DOI: 10.2210/pdb9dnq/pdb
• Related: 9DNO 9DNP 9DNR
• Descriptor: E3 ubiquitin-protein ligase UBR2, ARG-TYR-PHE-NH2, ZINC ION, ... (4 entities in total)
• Functional Keywords: ubr, e3 ligase, natural ligands, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 17834.30

Authors

Huang, S.,Wu, J.,Taylor, S.,Chen, Y. (deposition date: 2024-09-17, release date: 2025-08-13, Last modification date: 2026-02-25)

Primary citation

Huang, S.T.,Chen, D.H.,Ren, T.,Thomas, N.,Wu, J.,Sankaran, B.,Jones, R.,Taylor, S.,Chen, Y.
An alternative pocket for binding the N-degrons by the UBR1 and UBR2 ubiquitin E3 ligases.
Protein Sci., 34:e70248-e70248, 2025

PubMed Abstract: The UBR family of ubiquitin ligases binds to N-termini of their targets (known as N-degron) to induce their ubiquitination and degradation via a conserved domain known as UBR-box. UBR1 and UBR2 share the highest sequence homology among the family, and substantial structural studies were previously performed for substrate binding by the UBR-boxes of UBR1 and UBR2. Here, we describe a new pocket in the UBR-boxes of UBR1 and UBR2 for binding the second residues of N-degrons through determining five co-crystal structures of the UBR-boxes with various N-degron peptides. Together with binding affinities measured by fluorescence polarization, we show that the two highly homologous UBR-boxes can interact with the second residue of an N-degron differently. In addition, the UBR-boxes undergo different conformational changes when binding N-degrons. Furthermore, we demonstrate that the sidechain of the third amino acid of an N-degron has no contribution to binding the UBR-boxes. These findings represent a new conceptual advancement for the UBR E3 ligases and the new insights described here can be leveraged for developing their selective ligands for research and potential therapies.

PubMed: 40880185
DOI: 10.1002/pro.70248

Experimental method

X-RAY DIFFRACTION (1.22 Å)