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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain Yeojin Kim , Aleksandar Lučić , Christopher Lenz , Frederic Farges , Martin P. Schwalm , Krishna Saxena , Thomas Hanke , Peter G. Marples , Jasmin C. Aschenbrenner , Daren Fearon , Frank Von Delft , Andreas Kramer , Stefan Knapp Communications Chemistry 8 DOI: 10.1038/s42004-025-01574-3 Diamond Proposal Number(s): [29658] Open Access Show Abstract ▼ 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).	Jun 2025
I03-Macromolecular Crystallography	LOPAC library screening identifies suramin as a TRIM21 binder with a unique binding mode revealed by crystal structure Yeojin Kim , Stefan Knapp , Andreas Kramer Acta Crystallographica Section F Structural Biology Communications 81 DOI: 10.1107/S2053230X25000913 Open Access Show Abstract ▼ Abstract: Differential scanning fluorimetry screening of the Library of Pharmacologically Active Compounds (LOPAC) identified four hits for the PRYSPRY domain of the human E3 ligase tripartite motif-containing protein 21 (TRIM21). Isothermal titration calorimetry subsequently confirmed suramin as a binder with micromolar affinity. To further investigate the binding mechanism, mouse TRIM21 was used as a structural surrogate due to its improved protein stability and high sequence similarity to the human counterpart. A crystal structure of the complex refined at 1.3 Å resolution revealed a unique binding mode, providing new avenues for targeting TRIM21 and for the development of proteolysis-targeting chimeras (PROTACs).	Mar 2025

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