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| Home > Publications database > Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain. |
| Home > Publications database > Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain. |
| Journal Article | DKFZ-2025-01227 |
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2025
Macmillan Publishers Limited, part of Springer Nature
[London]
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Please use a persistent id in citations: doi:10.1038/s42004-025-01574-3
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).
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