9QFL の概要
| エントリーDOI | 10.2210/pdb9qfl/pdb |
| 分子名称 | YTH domain-containing family protein 2, 6-sulfanylidene-1,7-dihydropyrazolo[3,4-d]pyrimidin-4-one, GLYCEROL, ... (5 entities in total) |
| 機能のキーワード | inhibitor, m6a reader, rna binding protein |
| 由来する生物種 | Homo sapiens (human) |
| タンパク質・核酸の鎖数 | 2 |
| 化学式量合計 | 39472.31 |
| 構造登録者 | |
| 主引用文献 | Invernizzi, A.,Nai, F.,Bedi, R.K.,Vargas-Rosales, P.A.,Li, Y.,Bochenkova, E.,Herok, M.,Zalesak, F.,Caflisch, A. Discovery of YTHDF2 Ligands by Fragment-Based Design. Acs Bio Med Chem Au, 5:753-765, 2025 Cited by PubMed Abstract: -Adenosine methylation is the most abundant modification of mRNA. The three members of the YTH domain family proteins (YTHDF1-3) recognize in the cytoplasm the mA-RNA modification. We screened a library of about 500,000 fragments (i.e., molecules with 11-20 non-hydrogen atoms) by docking into YTHDF2, which resulted in the identification of six active compounds among 47 tested in vitro (hit rate of 13%). The acquisition of 28 analogues of the docking hits provided an additional set of 10 active compounds (IC < 100 μM). Protein crystallography-guided optimization of a ligand-efficient fragment by the synthesis of 32 derivatives culminated in a series of YTHDF2 ligands, which show low-micromolar affinity measured by a fluorescence polarization (FP) assay and a homogeneous time-resolved fluorescence-based (HTRF) assay. The series is characterized by very favorable ligand efficiency (of about 0.3-0.4 kcal/mol per non-hydrogen atom). Compound binds to YTHDF2 according to the FP and HTRF assays with a value of 1.3 μM and an IC value of 11 μM, respectively, and it is selective against all of the other YTH reader proteins. Several compounds of the series bind to the three YTHDF proteins with similar low-micromolar affinity, while they are less potent for YTHDC1 and YTHDC2. In contrast, compounds and bind also to YTHDC2, with of 6.3 and 4.9 μM, respectively. We also disclose six crystal structures of YTHDF2 in the complex with the fragments identified by docking. PubMed: 40860041DOI: 10.1021/acsbiomedchemau.5c00099 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.7 Å) |
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