9Q9P

TRIM21 PRYSPRY bound to compound 37

This is a non-PDB format compatible entry.

Summary for 9Q9P

• Entry DOI: 10.2210/pdb9q9p/pdb
• Descriptor: E3 ubiquitin-protein ligase TRIM21, (2~{S},4~{S})-1-[(3~{S})-3-azanyl-3-(2-methoxyphenyl)propanoyl]-4-cyclohexyl-~{N}-[(2~{S})-1-(methylamino)-1-oxidanylidene-3-pyridin-4-yl-propan-2-yl]pyrrolidine-2-carboxamide (3 entities in total)
• Functional Keywords: trim21, e3 ligase, protac, pryspry, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 23053.91

Authors

Luptak, J. (deposition date: 2025-02-26, release date: 2025-10-08, Last modification date: 2026-04-22)

Primary citation

Luptak, J.,Clift, D.,Mukadam, A.,Benn, J.,Rhinesmith, T.,McLaughlin, S.H.,Dodds, A.C.,Lapetaje, J.E.,Sczaniecka-Clift, M.,France, D.J.,McEwan, W.A.,James, L.C.
State-selective small molecule degraders that preferentially remove aggregates and oligomers.
Nat Commun, 16:10486-10486, 2025

PubMed Abstract: TRIM21 is a unique E3 ligase that uses a clustering-based activation mechanism to degrade complex multimeric substrates. This activity underpins the targeted protein degradation technology Trim-Away and genetically encoded degraders that selectively target aggregated tau protein and prevent tauopathy. Here we describe small molecules that mimic TRIM21's natural epitope and function as either effective inhibitors or potent and selective degraders called TRIMTACs. TRIMTACs mediate degradation as rapidly as PROTACs but can also selectively degrade specific protein pools depending on assembly state. We demonstrate the utility of this state-specific degradation by selectively removing the pro-inflammatory signalling protein Myd88 when assembled into the Myddosome and the cell-death protein RIPK3 when polymerised into the Necrosome. We further show that TRIMTACs can inhibit seeded tau aggregation under conditions where a PROTAC is ineffective. These results highlight that TRIM21's clustering-based activation can be exploited by small molecule degraders to carry out state-selective degradation of therapeutic targets.

PubMed: 41290659
DOI: 10.1038/s41467-025-65454-z

Experimental method

X-RAY DIFFRACTION (2.1 Å)