9II5

Crystal structure of human TRIM21 PRYSPRY in complex with compound 1

This is a non-PDB format compatible entry.

Summary for 9II5

• Entry DOI: 10.2210/pdb9ii5/pdb
• Descriptor: E3 ubiquitin-protein ligase TRIM21, ~{N}-[(1-fluoranylcyclohexyl)methyl]-~{N}-methyl-4-(2-methylsulfanylphenyl)-2-methylsulfonyl-benzamide (3 entities in total)
• Functional Keywords: complex, e3 ligase, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20643.27

Authors

Zhang, L.Y. (deposition date: 2024-06-19, release date: 2025-05-07, Last modification date: 2025-05-28)

Primary citation

Li, X.,Wang, Q.,Guo, A.,Qiu, Y.,Chen, Q.,Li, Y.,Zhang, L.,Guo, Y.,Meng, X.,Li, S.,Liu, G.,Zhang, L.,Liu, J.,Li, X.,Cai, L.,Cheng, X.,Liu, C.,Wang, X.,Wood, A.,Murray, J.,Liu, G.,Li, J.,Huang, X.,Dou, D.
Chemically Induced Nuclear Pore Complex Protein Degradation via TRIM21.
Acs Chem.Biol., 20:1020-1028, 2025

PubMed Abstract: Despite the exciting progress of bifunctional degrader molecules, also known as proteolysis-targeting chimeras (PROTACs), the rapidly expanding field is still significantly hampered by the lack of available E3 ligase ligands. Our research bridges this gap by uncovering a series of small-molecule ligands to the E3 ligase TRIM21 through DNA-Encoded Library (DEL) technology. We confirmed their interaction with TRIM21 using crystallography and demonstrated their antiproliferative effects across various cancer cell types. Furthermore, proteomic studies identified that the mRNA Export Factor GLE1 and the Nuclear Pore Complex Protein NUP155 were significantly downregulated on TRIM21 ligand treatment. This degradation required TRIM21 and was ubiquitin-proteasome-dependent. More specifically, NUP155 was the primary target for the TRIM21 ligands, while GLE1 was considered a passenger target on initial degradation of NUP155. Using immunofluorescence techniques, we further demonstrated that the degradation of GLE1 and NUP155 proteins impaired the integrity of the nuclear envelope, leading to cell death. Highlighted by this research, a novel mode of action has been discovered for the TRIM21 E3 ligase ligand, acting as a monovalent degrader that triggers de novo interaction with functional complex proteins and induces their degradation.

PubMed: 40247740
DOI: 10.1021/acschembio.4c00833

Experimental method

X-RAY DIFFRACTION (1.49 Å)