9Q9P9Q9P の概要
| エントリーDOI | 10.2210/pdb9q9p/pdb |
| 分子名称 | 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) |
| 機能のキーワード | trim21, e3 ligase, protac, pryspry, ligase |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 23053.91 |
| 構造登録者 | |
| 主引用文献 | 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 Cited by 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: 41290659DOI: 10.1038/s41467-025-65454-z 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.1 Å) |
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