9QBA

Human TRIM21 PRYSPRY domain in complex with AL236

これはPDB形式変換不可エントリーです。

9QBA の概要

• エントリーDOI: 10.2210/pdb9qba/pdb
• 分子名称: E3 ubiquitin-protein ligase TRIM21, ~{N}-(cyclohexylmethyl)-4-(4-fluoranyl-2-methylsulfanyl-phenyl)-2-methylsulfonyl-benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: trim21, pryspry domain, e3 ligase, inhibitor, 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: 20892.57

構造登録者

Kim, Y.,Lucic, A.,Knapp, S.,Kraemer, A.,Structural Genomics Consortium (SGC) (登録日: 2025-03-01, 公開日: 2025-03-12, 最終更新日: 2025-09-24)

主引用文献

Kim, Y.,Lucic, A.,Lenz, C.,Farges, F.,Schwalm, M.P.,Saxena, K.,Hanke, T.,Marples, P.G.,Aschenbrenner, J.C.,Fearon, D.,von Delft, F.,Kramer, A.,Knapp, S.
Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain.
Commun Chem, 8:185-185, 2025

PubMed Abstract: Tripartite motif-containing protein 21 (TRIM21), and particularly its PRY-SPRY protein interaction domain, plays a critical role in the immune response by recognizing intracellular antibodies targeting them for degradation. In this study, we performed a crystallographic fragment screening (CFS) campaign to identify potential small molecule binders targeting the PRY-SPRY domain of TRIM21. Our screen identified a total of 109 fragments binding to TRIM21 that were distributed across five distinct binding sites. These fragments have been designed to facilitate straightforward follow-up chemistry, making them ideal starting points for further chemical optimization. A subsequent fragment merging approach demonstrated improved activity. To enable functional validation of compounds with full length human TRIM21, we established a NanoBRET assay suitable for measuring target engagement to the main Fc binding site in life cells. The high-resolution structural data and observed binding modes across the different sites highlight the versatility of the PRY-SPRY domain as a target for small-molecule intervention. The presented data provide a solid foundation for structure-guided ligand design, enabling the rational design of more potent and selective compounds, with the goal to develop bivalent molecules such as Proteolysis Targeting Chimeras (PROTACs).

PubMed: 40514378
DOI: 10.1038/s42004-025-01574-3

実験手法

X-RAY DIFFRACTION (1.45 Å)