Kim Yeojin, Knapp Stefan, Krämer Andreas
Department of Pharmacy, Goethe University Frankfurt, Max-von-Laue Strasse 9, Frankfurt am Main, 60438 Hessen, Germany.
Acta Crystallogr F Struct Biol Commun. 2025 Mar 1;81(Pt 3):101-107. doi: 10.1107/S2053230X25000913. Epub 2025 Feb 16.
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).
通过差示扫描荧光法对药理活性化合物库（LOPAC）进行筛选，确定了人E3连接酶含三联基序蛋白21（TRIM21）的PRYSPRY结构域有四个命中化合物。随后等温滴定量热法证实苏拉明是一种具有微摩尔亲和力的结合剂。为了进一步研究结合机制，由于小鼠TRIM21具有更高的蛋白质稳定性且与人类对应物具有高度序列相似性，因此将其用作结构替代物。在1.3Å分辨率下精修得到的复合物晶体结构揭示了一种独特的结合模式，为靶向TRIM21和开发蛋白酶靶向嵌合体（PROTAC）提供了新途径。
