Crystallographic fragment screening reveals ligand hotspots in TRIM21 PRY-SPRY domain.

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 lengt

SUBMITTER: Kim Y 

PROVIDER: S-EPMC12166061 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature